+publisher:"Virginia Tech" +contributor:("Carlier, Paul R.")

Virginia Tech

1. Camerino, Eugene. Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae.

Degree: MS, Chemistry, 2013, Virginia Tech

► Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides.… (more)

Subjects/Keywords: acetylcholinesterase inhibitors; acetylcholine; transition-state analogues; trifluoromethyl ketones; insecticides; mosquitocides

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APA (6^th Edition):

Camerino, E. (2013). Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/54015

Chicago Manual of Style (16^th Edition):

Camerino, Eugene. “Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae.” 2013. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/54015.

MLA Handbook (7^th Edition):

Camerino, Eugene. “Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae.” 2013. Web. 07 Mar 2021.

Vancouver:

Camerino E. Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae. [Internet] [Masters thesis]. Virginia Tech; 2013. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/54015.

Council of Science Editors:

Camerino E. Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae. [Masters Thesis]. Virginia Tech; 2013. Available from: http://hdl.handle.net/10919/54015

Virginia Tech

2. Morris, Emily A. Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors.

Degree: MS, Chemistry, 2015, Virginia Tech

URL: http://hdl.handle.net/10919/73491

► Sphingosine 1-phosphate (S1P) has become a prevalent drug discovery target due to studies implicating it to several disease pathologies such as fibrosis, sickle cell disease,… (more)

▼ Sphingosine 1-phosphate (S1P) has become a prevalent drug discovery target due to studies implicating it to several disease pathologies such as fibrosis, sickle cell disease, inflammation, diabetes, and cancer. S1P functions to induce cell proliferation and migration. S1P signaling occurs through intracellular targets or transport outside of the cell via ABC transporters, where it acts as a ligand to G-protein coupled receptors (S1P1-5). Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to S1P; these are the only enzymes known to mediate the phosphoryl transfer. Inhibiting either or both SphKs helps to modulate S1P, which may be useful as a therapeutic avenue for disease states where S1P signaling has gone awry. Herein, we document our efforts in profiling the structure-activity relationships (SAR) of SphK2 through an iterative process of synthesis and biological testing. First, an SAR structured around the head and linker region of our lead molecule, SLR080811, was performed. SLR080811 has a Ki of 1.3 µM and is 5-fold selective for SphK2. The modifications performed on SLR080811 yielded two promising inhibitors: SLP120701 (SphK2 selective with a Ki of 1.2 µM) and SLP7111228 (>200 fold selective for SphK1 with a Ki of 48 nM). In vitro studies in U937 cells yielded a decrease in S1P levels with the introduction of inhibitors. Mouse studies provided insight into the pharmacokinetic effect of our SphK2-selective inhibitors, revealing an increase in S1P levels in the blood. When in vivo studies were performed with the SphK1 selective inhibitor, S1P levels in blood decreased. These molecules provide the chemical biology tools to determine the effect of modulating S1P levels in vivo. We also focused our investigation on the tail region of the pharmacophore. From this study, SLM6031434 and SLM6041418 were discovered and both proved to be more potent and selective SphK2 inhibitors than SLR080811. SLM6031434 has a Ki of 370 nM and is 23-fold selective for SphK2. SLM6041418 has a Ki of 430 nM and is 24-fold selective for SphK2. Consistent with our previous observations, in vitro studies showed a decrease in S1P levels when inhibitor was introduced. Similarly, in vivo studies resulted in an increase of S1P levels in the blood. These compounds are positioned towards animal models of disease. Advisors/Committee Members: Santos, Webster (committeechair), Kingston, David G. I. (committee member), Carlier, Paul R. (committee member).

Subjects/Keywords: sphingosine 1-phosphate; sphingosine kinase inhibitors; structure-activity relationships; guanidine inhibitors

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APA (6^th Edition):

Morris, E. A. (2015). Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/73491

Chicago Manual of Style (16^th Edition):

Morris, Emily A. “Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors.” 2015. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/73491.

MLA Handbook (7^th Edition):

Morris, Emily A. “Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors.” 2015. Web. 07 Mar 2021.

Vancouver:

Morris EA. Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors. [Internet] [Masters thesis]. Virginia Tech; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/73491.

Council of Science Editors:

Morris EA. Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors. [Masters Thesis]. Virginia Tech; 2015. Available from: http://hdl.handle.net/10919/73491

Virginia Tech

3. Wang, Ming. Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants.

Degree: MS, Chemistry, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/73742

► As part of an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project with the Natural Products Discovery Institute, four plant extracts were… (more)

Subjects/Keywords: natural product; antiproliferative; antiplasmodial; A2780; Plasmodium falciparum Dd2

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APA (6^th Edition):

Wang, M. (2016). Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/73742

Chicago Manual of Style (16^th Edition):

Wang, Ming. “Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants.” 2016. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/73742.

MLA Handbook (7^th Edition):

Wang, Ming. “Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants.” 2016. Web. 07 Mar 2021.

Vancouver:

Wang M. Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants. [Internet] [Masters thesis]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/73742.

Council of Science Editors:

Wang M. Isolation and Structure Elucidation of Antiproliferative and Antiplasmodial Natural Products from Plants. [Masters Thesis]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/73742

Virginia Tech

4. Jiang, Ying. Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species.

Degree: MS, Entomology, 2011, Virginia Tech

URL: http://hdl.handle.net/10919/41236

► Malaria (vector: Anopheles gambiae) is a major infectious disease that kills about 1 million people each year. For the improvement of its treatment and vector… (more)

▼ Malaria (vector: Anopheles gambiae) is a major infectious disease that kills about 1 million people each year. For the improvement of its treatment and vector control during the past decades, several issues such as high medicine cost, insecticide resistance, and lack of an effective vaccine have prevented adequate control of malaria. Additionally, the low selectivity of malaria vector insecticides also presents a public health problem. The purpose of developing novel carbamate insecticides in our laboratory is to offer effective and selective insecticide options to achieve the ultimate goal of malaria control. First, 50% inhibition concentration (IC50) data was collected from three mammalian AChEs with eight commercial carbamate insecticides by using the Ellman assay. The IC50 values varied from 57 nM to 7358 nM. The AChE sensitivity pattern and level were shown to be similar between the recombinant mouse and ICR male mouse brain cortex homogenate (slope = 0.99, R2 = 0.96). Then eight novel carbamate insecticides that are possible malaria vector control agents were selected for further neurotoxicity testing in non-target organisms. For commercial carbamate insecticides, the IC50 varied from 9.1 nM to 2,094 nM. For the novel carbamate insecticides, it varied from 58 nM to 388,800 nM. Based on IC50 data from previous work on A. gambiae, the selectivity index (IC50 of non-target species / IC50 A. gambiae) ranged from 0.17 to 5.64 and from 0.47 to 19,587 for commercial and novel carbamate insecticides, respectively. Subsequently, the AChE protein sequence alignment comparison and cladogram were used to compare the genetic and evolutionary relationship among five different organisms. The alignment score ranged from 88 for mouse vs. human to 54 for hen vs. T. californica. The evolutionary relationships among species was obtained from the cladogram. Recombinant mouse vs. recombinant human was shown to have the most similar inhibitor potency profiles (alignment score = 88, closest taxa position on cladogram, similar AChE sensitivity pattern [R2 = 0.81] and level [P > 0.05] to the novel carbamates). Neurotoxic esterase (NTE) assay showed that the novel carbamates did not significantly inhibit NTE, inhibition of which underlies a significant hazard for anticholinesterases, especially organophosphates, in several nontarget vertebrate organisms. The NTE activity in the presence of novel carbamate insecticides ranged from 93% to 116% of the control, while in the commercial group, bendiocarb significantly inhibited NTE, leaving only 76.5% of the initial reactivity at 1 mM inhibitor concentration. Further in vivo bioassay using Daphnia magna was conducted to compare the aquatic toxicity of commercial and novel carbamates. The data showed that except for PRC331 (3-tert-butylphenylmethylcarbamate), all novel carbamates were of similar potency as bendiocarb (LC50 = 611 nM) for aquatic toxicity, and their LC50 values ranged from 172 nM (PRC331) to 1109 nM. In conclusion, the novel carbamate insecticides would… Advisors/Committee Members: Bloomquist, Jeffrey R. (committeechair), Carlier, Paul R. (committee member), Mullins, Donald E. (committeecochair).

Subjects/Keywords: neurotoxic esterase; acetylcholinesterase; carbamate insecticides; neurotoxicity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jiang, Y. (2011). Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/41236

Chicago Manual of Style (16^th Edition):

Jiang, Ying. “Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species.” 2011. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/41236.

MLA Handbook (7^th Edition):

Jiang, Ying. “Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species.” 2011. Web. 07 Mar 2021.

Vancouver:

Jiang Y. Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species. [Internet] [Masters thesis]. Virginia Tech; 2011. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/41236.

Council of Science Editors:

Jiang Y. Evaluation of Novel Carbamate Insecticides for Neurotoxicity to Non-Target Species. [Masters Thesis]. Virginia Tech; 2011. Available from: http://hdl.handle.net/10919/41236

5. Liu, Lixuan. MMV008138 and analogs: potential novel antimalarial agents for P. falciparum.

Degree: MS, Chemistry, 2018, Virginia Tech

URL: http://hdl.handle.net/10919/95315

► Malaria is a severe and deadly mosquito-borne disease. Although treatable, the continuous emergence of multi-drug resistant parasite strains urgently calls for the development of novel… (more)

▼ Malaria is a severe and deadly mosquito-borne disease. Although treatable, the continuous emergence of multi-drug resistant parasite strains urgently calls for the development of novel antimalarial agents. P. falciparum parasites synthesize essential isoprenoid precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), via a non-mevalonate pathway: the methylerythritol phosphate (MEP) pathway. This pathway is not utilized by humans. Thus, compounds that target the MEP pathway and disrupt isoprenoid biosynthesis in P. falciparum hold promise as potent and safe new antimalarial agents, that engage new targets. Previously, we and others identified MMV008138 from the Malaria Box as a MEP pathway targeting compound. Later work revealed that it targets the IspD enzyme within the MEP pathway. Work in the Carlier group has established preliminary structure-activity relationship (SAR) of MMV008138: 1) (1R,3S)-configuration is required; 2) 2', 4'-disubstitution of the D-ring with small, electronegative substituents; 3) functional importance of carboxylate acid at C3. In this work, I aim to gain further insight into the C3 SAR and A-ring SAR of lead compound MMV008138. Synthesized acid bioisosteres and A-ring analogs of MMV008138 were evaluated in their ability to inhibit P. falciparum parasite growth. We showed that the C3 substituent of MMV008138 has a very tight SAR, and likely interacts with a very constricted pocket within the PfIspD enzyme. A-ring modifications are limited to certain positions of MMV001838 and need to be sterically small. However, we have yet to identify a modification that significantly improves drug lead potency. Future work will continue towards understanding the A-ring SAR of MMV008138, as well as D-ring SAR and C1-SAR. Efforts will also be directed towards finding analogs with improved potency, transport and metabolic stability. Advisors/Committee Members: Carlier, Paul R. (committeechair), Tanko, James M. (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: malaria; antimalarial; P. falciparum; MEP pathway; IspD; MMV008138; structure-activity relationship

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APA (6^th Edition):

Liu, L. (2018). MMV008138 and analogs: potential novel antimalarial agents for P. falciparum. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/95315

Chicago Manual of Style (16^th Edition):

Liu, Lixuan. “MMV008138 and analogs: potential novel antimalarial agents for P. falciparum.” 2018. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/95315.

MLA Handbook (7^th Edition):

Liu, Lixuan. “MMV008138 and analogs: potential novel antimalarial agents for P. falciparum.” 2018. Web. 07 Mar 2021.

Vancouver:

Liu L. MMV008138 and analogs: potential novel antimalarial agents for P. falciparum. [Internet] [Masters thesis]. Virginia Tech; 2018. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/95315.

Council of Science Editors:

Liu L. MMV008138 and analogs: potential novel antimalarial agents for P. falciparum. [Masters Thesis]. Virginia Tech; 2018. Available from: http://hdl.handle.net/10919/95315

Virginia Tech

6. Li, Hao. Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors.

Degree: PhD, Chemistry, 2019, Virginia Tech

URL: http://hdl.handle.net/10919/100741

► Sphingosine kinase 1 (SphK1) is the key enzyme catalyzing the formation of sphingosine-1-phosphate (S1P), which is an important signaling molecule that regulates multiple biological process… (more)

▼ Sphingosine kinase 1 (SphK1) is the key enzyme catalyzing the formation of sphingosine-1-phosphate (S1P), which is an important signaling molecule that regulates multiple biological process including inflammatory responses. Elevated SphK1 activity as well as upregulated S1P levels is linked to various diseases such as cancer, fibrosis and sickle cell disease. Therefore, there is a growing interest in studying SphK1 as a potential target for these diseases. Through high-throughput screening, various SphK1 inhibitors have been discovered, among which PF-543 is the most potent and selective inhibitor reported to date (Ki=3.6 nM, >100 fold selectivity for SphK1). Previous research indicated that SphK1 inhibitor PF-543 is effective in reducing S1P levels and slowing down the development of sickle cell disease in vivo. However, the lack of in vivo stability of PF-543 still makes it necessary to develop inhibitors with an improved pharmacokinetic profile. In this study, PF-543 was employed as the lead compound, and the influence of different tails groups and head groups on binding affinity and in vivo stability were investigated. In brief, (R)-prolinol-based derivatives with various tail groups including alkyl, alkoxy and biphenyl groups were synthesized. Their inhibition potency was tested in a broken-cell assay, and hit compounds were further evaluated in a yeast cell assay to determine EC50 values. The U937 cell line and mice model were utilized for hit compounds to quantify S1P reduction in vitro and in vivo. Our preliminary results indicated compound 2.14d was the best hit discovered, with 88% SphK1 inhibition at 1 μM. In addition, compound 2.14d with a Ki of 0.68 μM and an EC50 of 0.15 μM, reduced the S1P of U937 cells by 90% at 1 μM. Its analog with a shorter tail group, 2.14a, reduced plasma S1P levels by 20% in mice (10 mg/kg, 3 h). Further modification of the head group of 2.14d produced compound 3.14c bearing a secondary benzylamine head group, with an EC50 value of 0.39 μM and less in vivo activity (14% plasma S1P reduction at 10 mg/kg, 6 h). Advisors/Committee Members: Santos, Webster (committeechair), Lowell, Andrew Nesemann (committee member), Kingston, David G. I. (committee member), Carlier, Paul R. (committee member).

Subjects/Keywords: Sphingosine-1-phosphate; Sphingosine Kinase Inhibitor; Structure-Activity Relationship

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APA (6^th Edition):

Li, H. (2019). Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/100741

Chicago Manual of Style (16^th Edition):

Li, Hao. “Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors.” 2019. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/100741.

MLA Handbook (7^th Edition):

Li, Hao. “Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors.” 2019. Web. 07 Mar 2021.

Vancouver:

Li H. Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors. [Internet] [Doctoral dissertation]. Virginia Tech; 2019. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/100741.

Council of Science Editors:

Li H. Design, Synthesis, and Structure-Activity Relationship Investigation of Selective Sphingosine Kinase Inhibitors. [Doctoral Dissertation]. Virginia Tech; 2019. Available from: http://hdl.handle.net/10919/100741

7. Camerino, Eugene. Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae.

Degree: PhD, Chemistry, 2015, Virginia Tech

URL: http://hdl.handle.net/10919/73771

► Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides.… (more)

▼ Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides. With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors. In vitro assay studies demonstrate that tri- and difluoromethyl ketones can potentially inhibit An. gambiae AChE (AgAChE). These compounds inhibit the enzyme by making a covalent adduct with the catalytic serine of AChE. Trifluoromethyl ketones however are poor inhibitors of the G119S resistant mutant of AgAChE. However difluoromethyl ketones can inhibit G119S AgAChE and compound 3-10g showed an IC₅₀ value of 25.1 nM after 23h incubation time. Despite this potent inhibition of AgAChE, the tri-, di-, and (mono)fluoroketones showed very low toxicity to An. gambiae, perhaps due to hydration and rapid clearance. In an attempt to improve An. gambiae toxicity, oximes and oxime ethers of these compounds were prepared as potential prodrugs. These structures identified trifluoromethyl ketone oxime 3-2d as a potent toxin against both wild-type (G3-strain) and a multiply resistant (Akron) strain of An. gambiae. This compound is within 3-fold of the toxicity of propoxur to wild type An. gambiae (LC₅₀ values of 106 and 39 µg/mL, respectively). Most significantly, 3-2d was much more toxic than propoxur to multiply-resistant (Akron) strain An. gambiae (LC₅₀ = 112 and >5,000 µg/mL, respectively). However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism. Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur over 22 h at pH 7.7 or 5.5. The mechanism of action of 3-2d remains unknown. Our enzyme inhibition studies have demonstrated that 3-2d does not hydrolyze to the trifluoromethyl ketone 2-9d at pH 7.7. The high Akron toxicity of 3-2d and poor inhibition of G119S AgAChE by 2-9d argue against enzyme mediated conversion of 3-2d to 2-9d within the mosquito. Thus, we can rule out an AChE inhibition mechanism for toxicity. Additional experiments by our collaborator (Dr. Jeffrey Bloomquist, University of Florida) also rule out inhibition of mitochondrial respiration or agonism of the muscarinic acetylcholine receptor. Future work will address other potential insecticidal modes of action. Advisors/Committee Members: Carlier, Paul R. (committeechair), Etzkorn, Felicia A. (committee member), Santos, Webster (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: Acetylcholinesterase; trifluoromethyl ketones; difluoromethyl ketones; fluoromethyl ketones; Anopheles gambiae; insecticide treated nets; malaria; pyrazoles; propoxur; insecticide resistance; oxime; oxime ether

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APA (6^th Edition):

Camerino, E. (2015). Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/73771

Chicago Manual of Style (16^th Edition):

Camerino, Eugene. “Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae.” 2015. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/73771.

MLA Handbook (7^th Edition):

Camerino, Eugene. “Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae.” 2015. Web. 07 Mar 2021.

Vancouver:

Camerino E. Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae. [Internet] [Doctoral dissertation]. Virginia Tech; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/73771.

Council of Science Editors:

Camerino E. Fluoromethyl ketone prodrugs: Potential new insecticides towards Anopheles gambiae. [Doctoral Dissertation]. Virginia Tech; 2015. Available from: http://hdl.handle.net/10919/73771

Virginia Tech

8. Crumpton, Jason. Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/77076

► The utilization of click chemistry to perform inter- and intramolecular ligation on DNA has become ubiquitous in the literature. Advances in copper (I) stabilizing ligands… (more)

▼ The utilization of click chemistry to perform inter- and intramolecular ligation on DNA has become ubiquitous in the literature. Advances in copper (I) stabilizing ligands that prevent DNA degradation via redox pathways have provided nucleic acid researchers access to the efficiency and quantitative nature of the click reaction. The majority of ligation procedures in the literature are performed in solution after DNA assembly and modification with alkyne reporter groups. However, without specialty alkyne reagents that can be sequentially and selectively deprotected, the solution phase method requires that the click reaction be performed on all DNA-attached alkynes simultaneously. Therefore, the variability of the azide reagent is limited to a singular R group. However, performing the click reaction on DNA during synthetic elongation (immediately after each alkyne installation) allows for the possibility of performing multiple click reactions with variable azide reagents. Unfortunately, most solid phase click procedures require long reaction times or the utilization of microwave irradiation to accelerate the reaction. The development of methods for the ligation of azides to alkynes without the use of microwave irradiation on solid phase is potentially very useful. Herein, we report a simple, efficient, and robust solid phase synthetic method for the ligation of azido-diamondoids to the alkyne-modified phosphate backbone of DNA with click chemistry using [Cu(CH₃CN)₄]PF₆ without stabilizing ligand. Interestingly, it was found that as the size of diamondoid increased, a corresponding increase in melting temperature of hybridized duplexes was observed. The developed method has the potential to complement existing DNA ligation procedures for applications in biotechnology and diagnostics. Interest in peptides incorporating boronic acid moieties is increasing due to their potential as therapeutics/diagnostics for a variety of diseases such as cancer. The utility of peptide boronic acids may be expanded with access to vast libraries that can be deconvoluted rapidly and economically. Unfortunately, current detection protocols using mass spectrometry are laborious and confounded by boronic acid trimerization, which requires time consuming analysis of dehydration products. These issues are exacerbated when the peptide sequence is unknown, as with de novo sequencing, and especially when multiple boronic acid moieties are present. Thus, a rapid, reliable and simple method for peptide identification is of utmost importance. Herein, we report the identification and sequencing of linear and branched peptide boronic acids containing up to five boronic acid groups by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Protocols for preparation of pinacol boronic esters were adapted for efficient MALDI analysis of peptides. Additionally, a novel peptide boronic acid detection strategy was developed in which 2,5-dihydroxybenzoic acid (DHB) served as both matrix and derivatizing agent in a convenient, in situ,… Advisors/Committee Members: Santos, Webster L. (committeechair), Capelluto, Daniel G. S. (committee member), Etzkorn, Felicia A. (committee member), Carlier, Paul R. (committee member).

Subjects/Keywords: click chemistry; DNA; matrix; peptide sequencing; MALDI-MS

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APA (6^th Edition):

Crumpton, J. (2012). Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77076

Chicago Manual of Style (16^th Edition):

Crumpton, Jason. “Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77076.

MLA Handbook (7^th Edition):

Crumpton, Jason. “Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids.” 2012. Web. 07 Mar 2021.

Vancouver:

Crumpton J. Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77076.

Council of Science Editors:

Crumpton J. Click Chemistry on DNA and Targeting RNA structure with Peptide Boronic Acids. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/77076

Virginia Tech

9. Patil, Shradha Vasant. Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization.

Degree: PhD, Chemistry, 2013, Virginia Tech

URL: http://hdl.handle.net/10919/50658

► Functionalization of hydrocarbons via a free-radical based allyl transfer reaction using various allyl bromide substrates has been previously studied. The work described in this dissertation… (more)

▼ Functionalization of hydrocarbons via a free-radical based allyl transfer reaction using various allyl bromide substrates has been previously studied. The work described in this dissertation focuses on the replacement of Br by phthalimido-N-oxyl (PINO ) which helps make this chemistry environmentally friendly. To replace Br with PINO , replacement of previously used allyl-bromide substrates with new allyl-PINO substrates were necessary. Various allyl- PINO compounds were synthesized and the use of these allyl-phthalimido-N-oxyl (allyl-PINO) compounds for the functionalization of various alkyl aromatic hydrocarbons is demonstrated. Kinetic studies were performed to observe the efficiency of the new chain reaction compared to the previously reported studies with allyl-bromides. We recently discovered that these allyl substrates are useful for the functionalization of ethers and acetals. The functionalization of various cyclic and acyclic ethers was performed using these allyl transfer reactions. This reaction was also performed in-solution, which allowed us to perform these reactions at low reagent concentrations. Kinetic chain lengths were measured for these reactions. High chain lengths were observed for all used ethers. Kinetic studies to investigate the rate of radical addition-elimination processes were performed using laser flash photolysis and competition kinetics. These experiments helped us to measure the reactivity and selectivity of PINO as a chain carrier in comparison with Br . Additionally, a new competition experiment was designed to study the relative rate constant for the 􀈕-fragmentation process. For this experiment a novel substrate that contains two leaving groups, Br and PINO , was synthesized, and the relative rates of elimination of Br vs PINO were compared. Advisors/Committee Members: Tanko, James M. (committeechair), Carlier, Paul R. (committee member), Brewer, Karen J. (committee member), Castagnoli, Neal Jr. (committee member).

Subjects/Keywords: Allyl transfer; Phthalimido-N-oxyl radical; Radical additions; Hydrocarbons; Chain reactions

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APA (6^th Edition):

Patil, S. V. (2013). Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/50658

Chicago Manual of Style (16^th Edition):

Patil, Shradha Vasant. “Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization.” 2013. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/50658.

MLA Handbook (7^th Edition):

Patil, Shradha Vasant. “Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization.” 2013. Web. 07 Mar 2021.

Vancouver:

Patil SV. Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization. [Internet] [Doctoral dissertation]. Virginia Tech; 2013. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/50658.

Council of Science Editors:

Patil SV. Radical additions of hydrocarbons, ethers and acetals to alkenes via allyl transfer reaction: A new chain reaction for C-H bond functionalization. [Doctoral Dissertation]. Virginia Tech; 2013. Available from: http://hdl.handle.net/10919/50658

Virginia Tech

10. Spencer, Jared Nathaniel. Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways.

Degree: PhD, Chemistry, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/70920

► The dissociative electron transfer reactions of a series of α-epoxyketones and tetra-n-butylammonium acetate have been examined by electrochemical and computational techniques. Results for both the… (more)

▼ The dissociative electron transfer reactions of a series of α-epoxyketones and tetra-n-butylammonium acetate have been examined by electrochemical and computational techniques. Results for both the direct electrochemical (linear sweep voltammetry and convolution voltammetry) and indirect electrochemical (homogeneous redox catalysis) reductions of the epoxyketones are presented. In cases where the ring-closed radical anion generated by reduction of the epoxyketones is resonance stabilized (aromatic epoxyketones) the mechanism proceeds in a stepwise fashion, where the electron transfer and bond breaking reactions occur in sequential, discrete steps. On the other hand, where there is no additional resonance stabilization afforded to the ring-closed epoxide radical anion (aliphatic epoxyketones) the reaction proceeds in a concerted fashion, where electron transfer and ring cleavage occur simultaneously. The presence (or absence) of resonance stabilization in the ring-opened distonic radical anion plays little role in the kinetics of these dissociative electron transfers. Computations with the Density Functional Theory (B3-LYP and BHandH-LYP) on α-epoxyketones are also presented, and are in good agreement with the electrochemical results. The oxidative dissociative electron transfers of the acetate anion in "dry" and "wet" (0.5 M H2O) acetonitrile were also characterized with direct and indirect electrochemical experiments, again utilizing linear sweep voltammetry, convolution voltammetry, and homogeneous redox catalysis. There is a significant change in the observed oxidation potential of the anion upon addition of water, as well as an apparent decrease in the intrinsic barrier to the electron transfer. The possible transition from a concerted to stepwise mechanism for the dissociative electron transfer of acetate upon addition of water is examined - the electrochemical data is compared to theoretical models for both the concerted and stepwise processes. It is determined that the indirect electrochemical experiments do not proceed through an outer sphere electron transfer. Additionally, it is shown that the difference between the direct oxidation of acetate in anhydrous and wet acetonitrile is unlikely to be the result of transition from a purely concerted mechanism to a purely stepwise mechanism based on thermodynamic considerations. Advisors/Committee Members: Tanko, James M. (committeechair), Carlier, Paul R. (committee member), Troya, Diego (committee member), Gandour, Richard D. (committee member).

Subjects/Keywords: Dissociative electron transfer; Epoxyketones; Radical ions; Radical rearrangements

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APA (6^th Edition):

Spencer, J. N. (2016). Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/70920

Chicago Manual of Style (16^th Edition):

Spencer, Jared Nathaniel. “Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways.” 2016. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/70920.

MLA Handbook (7^th Edition):

Spencer, Jared Nathaniel. “Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways.” 2016. Web. 07 Mar 2021.

Vancouver:

Spencer JN. Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways. [Internet] [Doctoral dissertation]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/70920.

Council of Science Editors:

Spencer JN. Reductive and oxidative dissociative electron transfers: transition between the concerted and stepwise mechanistic pathways. [Doctoral Dissertation]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/70920

11. Childress, Elizabeth Saunders. Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers.

Degree: PhD, Chemistry, 2017, Virginia Tech

URL: http://hdl.handle.net/10919/86662

► Sphingosine 1-phosphate (S1P) is a cellular signaling molecule that has been implicated in a variety of diseases including cancer, fibrosis, Alzheimer's, and sickle cell disease.… (more)

▼ Sphingosine 1-phosphate (S1P) is a cellular signaling molecule that has been implicated in a variety of diseases including cancer, fibrosis, Alzheimer's, and sickle cell disease. It is formed from the phosphorylation of sphingosine (Sph) by sphingosine kinase (SphK) and SphK exists as two isoforms-"SphK1 and SphK2, which differ with respect to their cellular activity and localization. As the key mediators in the synthesis of S1P, SphKs have attracted attention as viable targets for pharmaceutical inhibition. To validate their potential as therapeutic targets, we aimed to develop potent, selective, and in vivo active inhibitors of SphK. Herein, we describe the design, synthesis and biological evaluation of SphK2 inhibitors. We first describe the development of six SphK2 inhibitors that assess the utility of replacing lipophilic tail groups with heterocyclic rings. These six compounds demonstrate that the lipid binding pocket for SphK2 cannot accommodate compounds with tail groups that are conformationally restricted or positively charged. We then describe the development of aminothiazole-based analogues of an SphK1-selective inhibitor. A library of 37 aryl-substituted aminothiazole tail groups were synthesized, revealing a structure-activity relationship study that examines electronic effects on the aryl-substituted aminothiazoles and the effect of modifying the amino portion of the aminothiazole. These molecules show surprisingly good potency and selectivity for SphK2. In particular, we highlight 3.20dd (SLC4101431), a biphenyl aminothiazole that is the post potent and selective SphK2 inhibitor to date, with an SphK2 Ki of 90 nM and 100-fold selectivity for SphK2. This molecule's in vivo activity will also be discussed. Mitochondrial uncouplers are small molecules that shuttle protons from the inter membrane space to the mitochondrial matrix independent of ATP synthase, which disrupts oxidative phosphorylation and promotes increased nutrient metabolism for homeostasis to be maintained. Consequently, small molecule mitochondrial uncouplers have been pursued as probes for mitochondrial function and as potential therapeutics for the treatment of obesity and type 2 diabetes. Herein, we describe the design, synthesis, and biological evaluation of small molecule mitochondrial uncouplers. We report a library of 52 compounds that have good mitochondrial uncoupling activity over a wide therapeutic range, including 5.16t (SHC4111522) and 5.17i (SHC4091665), which have EC50 values of 0.63 uM and 1.53 uM, respectively, and achieve at least 2-fold increase in oxygen consumption rates relative to basal levels. With these molecules, we demonstrate that pKa and cLogP significantly contribute to uncoupling activity and must be accounted for when developing new generation small molecule mitochondrial uncouplers. Advisors/Committee Members: Santos, Webster L. (committeechair), Gandour, Richard D. (committee member), Carlier, Paul R. (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: Structure-Activity Relationship; Sphingosine Kinase; Sphingosine 1-Phosphate; Mitochondrial Uncoupler; Protonophore; Oxygen Consumption Rate

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APA (6^th Edition):

Childress, E. S. (2017). Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/86662

Chicago Manual of Style (16^th Edition):

Childress, Elizabeth Saunders. “Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers.” 2017. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/86662.

MLA Handbook (7^th Edition):

Childress, Elizabeth Saunders. “Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers.” 2017. Web. 07 Mar 2021.

Vancouver:

Childress ES. Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers. [Internet] [Doctoral dissertation]. Virginia Tech; 2017. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/86662.

Council of Science Editors:

Childress ES. Structure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplers. [Doctoral Dissertation]. Virginia Tech; 2017. Available from: http://hdl.handle.net/10919/86662

Virginia Tech

12. Patwardhan, Neeraj Narendra. Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/37814

► The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are… (more)

▼ The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of C_α-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project. Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable C_α-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the "ate-complex" generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp²) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp³) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions. Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et₂O] was studied in order to predict the mechanism of this process in Et₂O solvent. Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1-magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies. Advisors/Committee Members: Carlier, Paul R. (committeechair), Santos, Webster L. (committee member), Tanko, James M. (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: enantiomerization; kinetics; chiral Grignard reagents; solvent effects; reaction order; ion-pair separation; entropy of activation; electrostriction; DFT calculations

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Patwardhan, N. N. (2012). Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/37814

Chicago Manual of Style (16^th Edition):

Patwardhan, Neeraj Narendra. “Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/37814.

MLA Handbook (7^th Edition):

Patwardhan, Neeraj Narendra. “Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents.” 2012. Web. 07 Mar 2021.

Vancouver:

Patwardhan NN. Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/37814.

Council of Science Editors:

Patwardhan NN. Study of Synthesis, Reactions and Enantiomerization of C_α-Chiral Grignard Reagents. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/37814

Virginia Tech

13. Valenciano Murillo, Ana Lisa. Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei.

Degree: PhD, Biochemistry, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/79769

► Trypanosoma brucei species are vector-borne protozoan parasites that cause Human African typanosomiasis (HAT) and nagana in cattle. In humans, the diseases caused by these parasites… (more)

▼ Trypanosoma brucei species are vector-borne protozoan parasites that cause Human African typanosomiasis (HAT) and nagana in cattle. In humans, the diseases caused by these parasites are fatal if left untreated. Treatments for these diseases are complicated because the approved drugs for treatment are ineffective against the parasites and have many toxic side effects associated with their use. There is a clear need to identify new therapeutics that are less toxic and more effective against T. brucei. Our approach for identifying new therapies is to identify novel targets in the parasite that can be modulated by small molecules. The mitogen-activated protein kinases (MAPK) pathway is a three-tiered signaling cascade that regulates cell responses to stimuli and are involved in essential processes. MAPKs can regulate differentiation, virulence, apoptosis, cell cycle and gene expression, which makes MAPKs interesting drug targets in T. brucei. The extracellular-signal regulated kinase 8 homolog in T. brucei (TbERK8) is essential for survival in bloodstream form T. brucei. The work in this dissertation involves characterizing this T. brucei MAPK to better understand its biological function and identify small molecules that can inhibit its activity to kill the parasite. Here, we report that TbERK8 is an atypical MAPK kinase that is able to autophosphorylate and no upstream kinases that activate TbERK8 have been identified. We have demonstrated that TbERK8 is able to phosphorylate the proliferating cell nuclear antigen homolog in T. brucei (TbPCNA). This is in contrast to the reported function the human ERK8 and PCNA homologs that form a stable complex in normal breast cells which does not result in PCNA phosphorylation. We also report here that TbPCNA is phosphorylated on three residues localized to a unique insertion loop by TbERK8. TbPCNA is tightly regulated in the parasites such that either upregulating or downregulating its expression arrests T. brucei proliferation. Although, this mechanism of phosphorylation is unique to TbPCNA, the role that such phosphorylation has in regulating TbPCNA is not known. Finally, we have identified small molecules that can selectively inhibit either TbERK8 or HsERK8, demonstrating that TbERK8 can be selectively inhibited to kill the parasite. The unique properties of TbERK8 can be exploited by small molecules that can be developed into new parasite-specific therapies that kill T. brucei with fewer side effects to the patients. Advisors/Committee Members: Mackey, Zachary Byron (committeechair), Carlier, Paul R. (committee member), Li, Jianyong (committee member), Cassera, Maria Belen (committee member).

Subjects/Keywords: Trypanosoma brucei; Extra-cellular signal regulated kinase 8 (ERK8); Proliferating cell nuclear antigen (PCNA); PIP-box; phosphorylation

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APA (6^th Edition):

Valenciano Murillo, A. L. (2016). Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/79769

Chicago Manual of Style (16^th Edition):

Valenciano Murillo, Ana Lisa. “Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei.” 2016. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/79769.

MLA Handbook (7^th Edition):

Valenciano Murillo, Ana Lisa. “Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei.” 2016. Web. 07 Mar 2021.

Vancouver:

Valenciano Murillo AL. Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei. [Internet] [Doctoral dissertation]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/79769.

Council of Science Editors:

Valenciano Murillo AL. Biological and biochemical characterization of the extracellular signal-regulated kinase 8 homolog (TbERK8) in Trypanosoma brucei. [Doctoral Dissertation]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/79769

Virginia Tech

14. Eaton, Alexander Lee. Isolation and Synthesis of Bioactive Compounds from Plants.

Degree: PhD, Chemistry, 2015, Virginia Tech

URL: http://hdl.handle.net/10919/64367

► As a part of a continuing search for bioactive compounds with the International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery… (more)

Subjects/Keywords: Natural Products; Antiproliferative; Antimalarial; Anti-inflammatory; Trihydroxyalkylcyclohexenones; Diterpene; Triterpene; Bis-5-alkylresorcinol; Synthesis

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APA (6^th Edition):

Eaton, A. L. (2015). Isolation and Synthesis of Bioactive Compounds from Plants. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/64367

Chicago Manual of Style (16^th Edition):

Eaton, Alexander Lee. “Isolation and Synthesis of Bioactive Compounds from Plants.” 2015. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/64367.

MLA Handbook (7^th Edition):

Eaton, Alexander Lee. “Isolation and Synthesis of Bioactive Compounds from Plants.” 2015. Web. 07 Mar 2021.

Vancouver:

Eaton AL. Isolation and Synthesis of Bioactive Compounds from Plants. [Internet] [Doctoral dissertation]. Virginia Tech; 2015. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/64367.

Council of Science Editors:

Eaton AL. Isolation and Synthesis of Bioactive Compounds from Plants. [Doctoral Dissertation]. Virginia Tech; 2015. Available from: http://hdl.handle.net/10919/64367

15. Snead, Russell Franklin. Development of Novel, Regioselective Borylation Protocols.

Degree: PhD, Chemistry, 2018, Virginia Tech

URL: http://hdl.handle.net/10919/85003

► Organoboron compounds are highly valued synthetic intermediates due to their diverse array of reactivity, which is often utilized in the synthesis of valuable organic molecules.… (more)

▼ Organoboron compounds are highly valued synthetic intermediates due to their diverse array of reactivity, which is often utilized in the synthesis of valuable organic molecules. For this reason, there is significant interest in the development of novel borylation protocols, especially those whose products are suitable for further synthetic transformations towards valuable classes of compounds. Research in organoboron synthesis has been geared heavily toward transition metal-catalyzed addition to double and triple bonds, though an increasing number of publications detail transition metal-free borylation techniques involving substrate-mediated activation of a diboron reagent. This dissertation describes the author's contributions to the development of both a transition metal-catalyzed diboration and a transition metal-free protoboration. A transition metal-free diboration of alkynamides is described in Chapter 1 which uses the unsymmetrical, differentially protected diboron reagent, pinBBdan. The method installs both boron moieties in a regio- and stereoselective fashion. The products have synthetic value because they are shown to have chemoselectivity in downstream cross-coupling reactions; chemoselectivity is made possible by to the significant difference in Lewis acidity of the pinacol and diaminonapthalene-protected boron centers. This method allows for facile synthesis of tetrasubstituted alkenes with a set geometry about the double bond. A protoboration of allenes employing a Cu(II) catalyst under aqueous and atmospheric conditions is described. Though Cu(I)-catalyzed allene protoboration is well-described in the literature, this is the first report of an analogous Cu(II)-mediated process. The selectivity of the reaction is ligand-controlled, and moderate to good regioselectivities and yields can be achieved through use of a triphenylphosphine as ligand. The method is an environmentally friendly and facile means by which to borylate a challenging cumulated substrate. Advisors/Committee Members: Santos, Webster L. (committeechair), Kingston, David G. I. (committee member), Tanko, James M. (committee member), Carlier, Paul R. (committee member).

Subjects/Keywords: borylation; transition metal-catalyzed; transition metal-free; allenes; alkynamides

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APA (6^th Edition):

Snead, R. F. (2018). Development of Novel, Regioselective Borylation Protocols. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/85003

Chicago Manual of Style (16^th Edition):

Snead, Russell Franklin. “Development of Novel, Regioselective Borylation Protocols.” 2018. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/85003.

MLA Handbook (7^th Edition):

Snead, Russell Franklin. “Development of Novel, Regioselective Borylation Protocols.” 2018. Web. 07 Mar 2021.

Vancouver:

Snead RF. Development of Novel, Regioselective Borylation Protocols. [Internet] [Doctoral dissertation]. Virginia Tech; 2018. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/85003.

Council of Science Editors:

Snead RF. Development of Novel, Regioselective Borylation Protocols. [Doctoral Dissertation]. Virginia Tech; 2018. Available from: http://hdl.handle.net/10919/85003

Virginia Tech

16. Pham, Ngoc Nhu. Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti.

Degree: MSin Life Sciences, Entomology, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/71699

► Mosquitoes affect human health worldwide as a result of their ability to vector multiple diseases. Mosquitocide resistance is a serious public health challenge that warrants… (more)

▼ Mosquitoes affect human health worldwide as a result of their ability to vector multiple diseases. Mosquitocide resistance is a serious public health challenge that warrants the development of improved chemical control strategies for mosquitoes. Previous studies demonstrate the mosquito blood-brain barrier (BBB) to interfere with the target-site delivery and action of anticholinesterase chemistries. The ATP-binding cassette (ABC) transporters are efflux proteins that assist in maintaining the BBB interface and serve as a first line of defense to mosquitocide exposures. To date, there are three subfamilies (ABC -B, -C, -G) of ABC transporters; however, knowledge of these chemistries interacting with mosquito ABC transporter(s) is limited. Here, I report that tacrine and bis(7)-tacrine are relative non-toxic anticholinesterases at solubility limits; however, the addition of verapamil enhances toxicity of both tacrine and bis(7)-tacrine to mosquitoes. Verapamil significantly increases the mortality of mosquitoes exposed to tacrine and bis(7)-tacrine compared to the tacrine- and bis(7)- tacrine-only treatments. Tacrine and bis(7)-tacrine reduce acetylcholinesterase activity in mosquito head preparations compared to the untreated mosquitoes; however, the addition of verapamil significantly increases the anticholinesterase activity of tacrine and bis(7)-tacrine compared to the tacrine-and bis(7)-tacrine-only treatments. Tacrine and bis(7)-tacrine increase ATPase activity in Aedes aegypti at lower concentrations compared to that of verapamil (Fig. 3). The differential increase in ATPase activity suggests that tacrine and bis(7)-tacrine are more suitable substrates for ABC transporter(s) compared to verapamil and, thus, provides putative evidence that ABC transporter(s) is a pharmacological obstacle to the delivery of these anticholinesterases to their intended target site. Advisors/Committee Members: Anderson, Troy D. (committeechair), Paulson, Sally L. (committee member), Brewster, Carlyle C. (committee member), Carlier, Paul R. (committee member), Li, Jianyong (committee member).

Subjects/Keywords: mosquito; tacrines; verapamil; acetylcholinesterase ATPase activity; ABC transporter

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APA (6^th Edition):

Pham, N. N. (2016). Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/71699

Chicago Manual of Style (16^th Edition):

Pham, Ngoc Nhu. “Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti.” 2016. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/71699.

MLA Handbook (7^th Edition):

Pham, Ngoc Nhu. “Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti.” 2016. Web. 07 Mar 2021.

Vancouver:

Pham NN. Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti. [Internet] [Masters thesis]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/71699.

Council of Science Editors:

Pham NN. Toxicological Analysis of Tacrines and Verapamil on the Yellow Fever Mosquito, Aedes aegypti. [Masters Thesis]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/71699

Virginia Tech

17. Sizovs, Antons. Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/77089

► The delivery of nucleic acids remains the major obstacle for nucleic acid-based therapies such as gene therapy and gene silencing therapies based on RNA interference.… (more)

▼ The delivery of nucleic acids remains the major obstacle for nucleic acid-based therapies such as gene therapy and gene silencing therapies based on RNA interference. In this dissertation we have developed and studied nucleic acid delivery vehicles based on cationic diblock glycopolymers that contain glucosamine and trehalosamine. Practical procedures were developed to synthesize 2-methacrylamido-2-deoxy glucose and 6-methacrylamido-6-deoxy trehalose starting with commercially available carbohydrates and utilizing trimethylsilyl protecting group chemistry. These monomers were polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization to yield glycopolymers with the desired lengths and low polydispersity indexes. Glycopolymers were chain-extended with aminoethylmethacrylamide to produce cationic diblock copolymers. The ability of cationic diblock copolymers to bind nucleic acids was demonstrated with gel electrophoresis and heparin exclusion assays. Complexes of the synthesized polymers with nucleic acids were studied with dynamic light scattering to reveal nanoparticles of 100-250 nm that were stable in the presence of serum proteins. Quartz crystal microbalance experiments showed that serum proteins adsorb on polytrehalose coated gold surfaces and it was suggested that these interactions may help mask the polytrehalose coated nanoparticles from potential actions of the immune system. Polytrehalose was also shown to suppress water crystallization similarly to trehalose by lowering the energies associated with the water/ice phase transition. The property was utilized to freeze-dry siRNA containing polyplexes which could be re-dissolved in water after lyophilization to yield nanoparticles. The polyplexes formulated with cationic diblock copolymers were shown to efficiently enter cervical cancer cells (HeLa cell line) and glioblastoma cells (U-87 cell line) and to deliver their nucleic acid cargo. Polyglucose-containing polymers were efficient mediators of exogenous gene expression in HeLa cells, and polytrehalose- containing polymers were effective in promoting the target gene down-regulation via RNA interference by delivered siRNA. Advisors/Committee Members: Reineke, Theresa Marie (committeechair), Madsen, Louis A. (committee member), Gibson, Harry W. (committee member), Riffle, Judy S. (committee member), Carlier, Paul R. (committeecochair).

Subjects/Keywords: RAFT; Gene Delivery; Polytrehalose; Nanoparticle; Polyglucose

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APA (6^th Edition):

Sizovs, A. (2012). Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77089

Chicago Manual of Style (16^th Edition):

Sizovs, Antons. “Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77089.

MLA Handbook (7^th Edition):

Sizovs, Antons. “Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery.” 2012. Web. 07 Mar 2021.

Vancouver:

Sizovs A. Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77089.

Council of Science Editors:

Sizovs A. Development of Carbohydrate-based Diblock Polymers for Nucleic Acid Delivery. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/77089

Virginia Tech

18. Raje, Mithun. Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/77051

► Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell proliferation. SphK phosphorylates sphingosine to form sphingosine-1-phosphate… (more)

Subjects/Keywords: reductive amination; structure-activity relationships; guanidine inhibitors; sphingosine-1-phosphate; sphingosine kinase inhibitors

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APA (6^th Edition):

Raje, M. (2012). Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77051

Chicago Manual of Style (16^th Edition):

Raje, Mithun. “Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77051.

MLA Handbook (7^th Edition):

Raje, Mithun. “Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors.” 2012. Web. 07 Mar 2021.

Vancouver:

Raje M. Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77051.

Council of Science Editors:

Raje M. Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/77051

Virginia Tech

19. Kizjakina, Karina. Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery.

Degree: PhD, Chemistry, 2011, Virginia Tech

URL: http://hdl.handle.net/10919/77127

► The delivery of nucleic acids at the tissue and cellular levels remains one of the major hurdles in this scientific area. Since nucleic acids are… (more)

▼ The delivery of nucleic acids at the tissue and cellular levels remains one of the major hurdles in this scientific area. Since nucleic acids are bulky macromolecules and unstable in the presence of nucleases, vehicles are required to compact them into nanosized particles, offer protection from degradation in vivo, and release the therapeutic cargo at the desired location. Polycationic vehicles are good candidates for these purposes since they can be chemically modified to tune the desired properties in nanoparticle formulations. We designed a family of trehalose-oligoethyleneamine copolymers that showed promising plasmid DNA (pDNA) transfection results in the presence of serum proteins. A diazidotrehalose monomer was copolymerized with linear oligoethyleneamines of varying length and containing alkyne end-groups via step-growth Cu(I)-catalyzed azide-alkyne cycloaddition polymerization resulting in a series of trehalose copolymers with a range of secondary amines (from 4 to 6) within the polymer backbone. Upon electrostatic complexation of the polycations and pDNA in aqueous media, nanosized particles were formed, and their sizes and zeta-potentials were characterized via dynamic light scattering (DLS). The glycopolymers were tested for pDNA binding, toxicity, cellular uptake, and transfection efficiency in vitro. Characterization of these polymers revealed a significant influence of minor structural modifications on bioactivity. In general, all of the polymers efficiently bind pDNA at low nitrogen to phosphate (N/P) ratios forming nanoparticles below 100 nm in size and demonstrated cellular uptake and transfection. Polymers comprised of trehalose moieties and four secondary amines in the repeat unit showed the greatest promise in pDNA delivery in vitro. Because of its large hydration volume, we hypothesize that trehalose contributes to particle stabilization in serum. The trehalose-based polymers with four secondary amines (Tr4) were subsequently modified with PEG (5kDa). This modification lead to the development of well-defined polymeric structures with PEG moieties selectively incorporated at the ends of linear trehalose-oligoethyleneamine polycations. The study of the effect of this modification on bioactivity revealed that there were no significant difference in the toxicity profiles within this series of PEGylated and non-PEGylated materials; however, overall results suggest that both modified and unmodified trehalose-oligoethyleneamine copolymers have a great promise for stem cell-based and regenerative therapies. Advisors/Committee Members: Reineke, Theresa Marie (committeechair), Roman, Maren (committee member), Edgar, Kevin J. (committee member), Carlier, Paul R. (committee member), Turner, S. Richard (committee member).

Subjects/Keywords: PEG; trehalose; nucleic acid delivery; glycopolymers; oligoethyleneamines

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APA (6^th Edition):

Kizjakina, K. (2011). Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77127

Chicago Manual of Style (16^th Edition):

Kizjakina, Karina. “Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery.” 2011. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77127.

MLA Handbook (7^th Edition):

Kizjakina, Karina. “Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery.” 2011. Web. 07 Mar 2021.

Vancouver:

Kizjakina K. Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery. [Internet] [Doctoral dissertation]. Virginia Tech; 2011. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77127.

Council of Science Editors:

Kizjakina K. Serum Stable Carbohydrate-Oligoethyleneamine Copolymers for Nucleic Acid Delivery. [Doctoral Dissertation]. Virginia Tech; 2011. Available from: http://hdl.handle.net/10919/77127

20. Richoux Jr, Gary Michael. Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates.

Degree: PhD, Chemistry, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/71675

► The self-regeneration of stereocenters via stereolabile axially-chiral intermediates (SRSvSACI) is a synthetic strategy in which the configuration of a starting material, possessing only a single… (more)

▼ The self-regeneration of stereocenters via stereolabile axially-chiral intermediates (SRSvSACI) is a synthetic strategy in which the configuration of a starting material, possessing only a single stereocenter, directs the formation of a chiral axis in an intermediate. The reaction proceeds stereospecifically, although the original stereocenter is destroyed through trigonalization. This is due to the stereochemical information encoded in the chiral axis, which is transformed into the configuration of a stereocenter in the product. In this research, we investigate the generation of axially chiral intermediates arising from both (S)-methyl lactate derivatives and 1,4-benzodiazepin-2,5-dione derivatives. For the deprotonation/alkylation of O-Bn and O-TBS substituted (S)-methyl lactate derivatives containing achiral oxazolidinones, we hypothesized that a twisted amide enolate featuring a chiral C(O-)-N axis could sufficiently impart stereochemical information and control the selectivity of the reaction. Previous work completed by Kobayashi showed in related compounds (E)- vs (Z)-enolate formation could be controlled through the identity of the 2'-oxygen substituent with –Bn affording the (E)-enolate and –TBS affording the (Z)-enolate. We investigated the utilization of achiral oxazolidinone moieties to selectively generate axial chiral intermediates that could then control the facial selectivity of sequential alkylations. Unfortunately, unforeseen synthetic difficulties prevented successful accomplishment of our project goals. We also utilized axially chiral intermediates in the generation of 3,3-disubstituted quinolone-2,4-diones. The target compounds serve as potentially useful drug scaffolds, yet synthetic access to them has remained limited due to the lack of commercial availability of the corresponding enantiopure quaternary substituted amino acids. Prior work in the Carlier group demonstrated the preferential (M)-conformer deprotonation demonstrated by 1,4-benzodiazepin-2,5-diones, and through the installation of an N4-tert-butyloxycarbonyl protecting group, we were able to take advantage of this preferential (M)-conformer deprotonation and generate 3,3-disubstituted quinolone-2,5-diones through an acyl-amino variant of the Chan rearrangement. In general, these reactions were highly enantioselective proceeding with little to no loss of enantiomeric excess. Finally, we collaborated with Professor Bloomquist to test the topical toxicity of selected ring-contracted products against adult Anopheles gambiae, the African vector of malaria. Advisors/Committee Members: Carlier, Paul R. (committeechair), Etzkorn, Felicia A. (committee member), Kingston, David G. I. (committee member), Santos, Webster (committee member).

Subjects/Keywords: Memory of Chirality; benzodiazepine; rearrangement; SRSvSACI

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APA (6^th Edition):

Richoux Jr, G. M. (2016). Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/71675

Chicago Manual of Style (16^th Edition):

Richoux Jr, Gary Michael. “Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates.” 2016. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/71675.

MLA Handbook (7^th Edition):

Richoux Jr, Gary Michael. “Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates.” 2016. Web. 07 Mar 2021.

Vancouver:

Richoux Jr GM. Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates. [Internet] [Doctoral dissertation]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/71675.

Council of Science Editors:

Richoux Jr GM. Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates. [Doctoral Dissertation]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/71675

Virginia Tech

21. Ghavami, Maryam. Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs.

Degree: PhD, Chemistry, 2018, Virginia Tech

URL: http://hdl.handle.net/10919/96192

► Worldwide, malaria is one of the deadliest diseases. In 2016 it sickened 216 million people and caused 445,000 deaths. In order to control the spread… (more)

▼ Worldwide, malaria is one of the deadliest diseases. In 2016 it sickened 216 million people and caused 445,000 deaths. In order to control the spread of this deadly diseases to human, we can either target the mosquito vector (Anopheles gambiae) or the parasite (Plasmodium falciparum). Due to recent emergence of resistance to current insecticides and antimalarial drugs there is a pressing need to discover and develop new agents that engage new targets in these organisms. To circumvent the effect of resistance to pyrethroid insecticides on the efficacy of insecticide treated nets (ITNs), the use of acetylcholinesterase (AChE) inhibitors on ITNs has drawn attention. In the first project, we explored a small library of g- substituted oxoisoxazole- 2(3H)-carboxamides and isoxazol-3-yl carbamates, and nitriles as AChE inhibitors targeting wild- type (G3) and resistant (Akron) An. gambiae mosquito. In total 23 compounds were synthesized and evaluated. Both carbamates and carboximides with a 2-cyclopropylethyl side chain (1-87a and 1-88a) were extremely toxic to Akron mosquitos, yet these compounds did not exhibit appreciable selectivity between human and An. gambiae AChE. Unfortunately, none of the nitriles showed appreciable toxicity to G3 strain of the mosquitoes, nor did they inhibit An. gambiae AChE. In the second project, conducted in collaboration with Professor Michael Klemba, we focused on the mode of action of an established antimalarial drug, Mefloquine (MQ). Dr. Klemba's recently developed amino acid efflux assay was used to determine the effect of MQ and its open-ring analogs on hemoglobin endocytosis and catabolism in P. falciparum-infected erythrocytes. In total 26 MQ analogs were synthesized and 18 were studied in depth to determine their potency to inhibit leucine (Leu) efflux and parasite growth (SYBR Green). An excellent correlation (R2 = 0.98) over nearly 4 log units was seen for these 18 compounds in the two assays. These data are consistent with the hypothesis that the antimalarial action of these compounds principally derives from inhibition of hemoglobin endocytosis. After this observation, a number of photo-affinity probes were designed and synthesized in hopes of isolating the molecular target of MQ. These analogs are currently being used by Dr. Klemba in pull-down experiments. In the third project, conducted in collaboration with Professor Belen Cassera, we sought to optimize a new antimalarial drug lead that would circumvent current resistance mechanisms. In Plasmodium parasites, the methylerythritol phosphate (MEP) pathway is known to be essential for its growth. This pathway is absent in humans, presenting the opportunity to develop potentially safe and effective therapeutic candidates. Previous work in the Cassera and Carlier lab had established that MMV008138 was the only compound in the Malaria Box that targeted the MEP pathway and that it was (1R,3S)-configured. My research expanded previous efforts in the Carlier group and produced synthesis of 73 analogs of MMV008138 (3-21a'1) that… Advisors/Committee Members: Carlier, Paul R. (committeechair), Kingston, David G. I. (committee member), Santos, Webster (committee member), Tanko, James M. (committee member).

Subjects/Keywords: Malaria; Antimalarial; Acetylcholinesterase; Heterocyclic carbamates and carboxamides; Nitriles; Mefloquine; Mode of action; Leu efflux; Photo affinity probe; IspD; MEP pathway; MMV008138; Structure- activity relationship

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ghavami, M. (2018). Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/96192

Chicago Manual of Style (16^th Edition):

Ghavami, Maryam. “Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs.” 2018. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/96192.

MLA Handbook (7^th Edition):

Ghavami, Maryam. “Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs.” 2018. Web. 07 Mar 2021.

Vancouver:

Ghavami M. Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs. [Internet] [Doctoral dissertation]. Virginia Tech; 2018. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/96192.

Council of Science Editors:

Ghavami M. Antimalarial Agents: New Mechanisms of Actions for Old and New Drugs. [Doctoral Dissertation]. Virginia Tech; 2018. Available from: http://hdl.handle.net/10919/96192

Virginia Tech

22. Verma, Astha. Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae.

Degree: PhD, Chemistry, 2014, Virginia Tech

URL: http://hdl.handle.net/10919/64294

► Malaria is one of the deadliest diseases known to mankind. In 2010, 219 million cases were reported, and 666,000 deaths were attributed to this disease.… (more)

▼ Malaria is one of the deadliest diseases known to mankind. In 2010, 219 million cases were reported, and 666,000 deaths were attributed to this disease. In the past, pyrethroid-treated mosquito nets have shown efficacy in reducing malaria transmission in many malaria endemic regions. However, an upsurge in the mosquito population that is resistant to pyrethroids threatens to compromise the efficacy of pyrethroid-treated bed nets. In an effort to develop another class of insecticide with a different mode of action, we have explored three classes of five membered heterocyclic carbamates (isoxazol-3-yl, pyrazol-5-yl, and pyrazol-4-yl), and 3-oxoisoxazole- 2(3H)-carboxamide as acetylcholinesterase inhibitors (AChE) targeting wild type (G3) and resistant (Akron) malaria mosquito Anopheles gambiae (Ag). Isoxazole carboxamide and carbamates were obtained regioselectively through judicious use of two different protocols. The final products were characterized and identified using 1H and 13C NMR, and mass spectroscopy. In addition, the carboxamide structure was confirmed using X-ray diffraction. Several of the novel carbamates and carboxamides evaluated exhibited excellent toxicity towards susceptible G3 and resistant Akron strain An. gambiae (48f LC50 G3 = 41 μg/mL, LC50 Akron = 58 μg/mL, and 47i LC50 G3 = 38 μg/mL, LC50 Akron = 40 μg/mL). Hence, achieving the resistance- breaking goal. On the contrary, the commercial aryl methylcarbamates currently approved for indoor residual sprays (IRS) showed no potency towards the resistant strain An. gambiae (LC50 G3 = 16-42 μg/mL, and LC50 Akron >5,000 μg/mL). Further, we observed low toxicological cross-resistance ratios (RR) for the toxic isoxazol-3-yl and pyrazol-4-yl carbamates, and 3- oxoisoxazole-2(3H)-carboxamides (RR = 0.5-2.0). Amongst the commercial AChE inhibitors approved for IRS, only aldicarb exhibited such low RR (RR = 0.5), whereas the RR for commercial aryl methylcarbamates exceed 130-fold. The low RR observed for these novel heterocyclic inhibitors would certainly be favorable for a new anticholinesterase-based mosquitocide targeting both the susceptible and resistant strain mosquitoes. Although the overall selectivity (Ag vs human) did not exceed 24-fold, the heterocyclic carbamates and carboxamides synthesized by the author showed appreciable inhibition of resistant AChE (G119S) in comparison to commercial aryl carbamates, which showed no inhibition at all. During the course of this project, the isoxazol-3-yl and pyrazol-5-yl methylcarbamates proved to be unstable, and thus could not be isolated. The synthesis of pyrazol-4-yl methylcarbamates using N-methylcarbamoyl chloride proved particularly challenging due to the formation of by-products called allophanates. The similar Rf of the by-product and the desired final product made the isolation laborious and time-consuming. We have successfully overcome this problem by employing a new protocol, where triphosgene served as the carbonylating agent and N-methylamine in THF was used as the amine source. In addition, we… Advisors/Committee Members: Carlier, Paul R. (committeechair), Kingston, David G. I. (committee member), Santos, Webster (committee member), Tanko, James M. (committee member).

Subjects/Keywords: Acetylcholinesterase; 1; 2-azoles; Anopheles gambiae; heterocyclic carbamates and carboxamides; isoxazole; insecticide treated nets; malaria; pyrazoles; propoxur; insecticide resistance; species-selective inhibitors.

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APA (6^th Edition):

Verma, A. (2014). Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/64294

Chicago Manual of Style (16^th Edition):

Verma, Astha. “Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae.” 2014. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/64294.

MLA Handbook (7^th Edition):

Verma, Astha. “Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae.” 2014. Web. 07 Mar 2021.

Vancouver:

Verma A. Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae. [Internet] [Doctoral dissertation]. Virginia Tech; 2014. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/64294.

Council of Science Editors:

Verma A. Small Core Heterocyclic Carbamates and Carboxamides: Resistance-breaking Acetylcholinesterase Inhibitors Targeting the Malaria Mosquito, Anopheles gambiae. [Doctoral Dissertation]. Virginia Tech; 2014. Available from: http://hdl.handle.net/10919/64294

Virginia Tech

23. Zhang, Jianyuan. Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application.

Degree: PhD, Chemistry, 2014, Virginia Tech

URL: http://hdl.handle.net/10919/25290

► Endohedral metalofullerenes (EMFs) have emerged as an important class of nanomaterials with vast promise in applications of molecular devices and nanomedicines. This dissertation addresses the… (more)

▼ Endohedral metalofullerenes (EMFs) have emerged as an important class of nanomaterials with vast promise in applications of molecular devices and nanomedicines. This dissertation addresses the EMF research span from synthesis to application, with an emphasis of work on trimetallic nitride template (TNT) EMF and carbide clusterfullerenes (CCFs). As a general introduction, chapter 1 reviews the main literature in TNT EMF studies. Also key works in CCF area are highlighted to show the common feature and uniqueness of this class of EMF in comparison with other EMFs. In the last part of the chapter a list of milestone progress in EMF area has been summarized. Chapter 2 is devoted to the synthetic work on EMFs. Especially, for isotopic modification, the trial and actual EMF syntheses in efforts to introduce 13C, 89Y and 177Lu are described. The next three chapters address the structural characterization of EMFs. Chapter 3 focuses on structural studies of CCFs. With detailed interpretation of 13C NMR and DFT computational results for selected members of the [email protected] family, the influence of fullerene cage on the size and shape of the yttrium carbide cluster (Y2C2)4+ is investigated. It has also been established that the carbide cluster prefers a linear shape in sufficiently large fullerene cages but adopts a compressed butterfly shape in smaller cages where space is constrained. Chapter 4 presents a systemic examination of dipole moments in TNT EMFs. The first 13C NMR study of [email protected](22010)-C78 is achieved on [email protected](22010)-C78. In addition, dipole moments of the [email protected] (n=39-44) family are probed by interpretation of chromatographic retention behavior, DFT computational results and single-crystal data. It has been found that TNT EMFs with pentalene motifs exhibit enhanced dipole moments due to the cluster-cage interplay. Chapter 5 provides full characterization of the [email protected](51383)-C84 (M=Y, Gd) molecule, which contains the first example of an asymmetric fullerene cage with fused pentagons. Furthermore, it is suggested that the C1(51383)-C84 cage is capable of a cascade of rearrangements into high symmetry and stable fullerene cages via well-established mechanistic steps, namely, extrusion of C2 units from pentalene or indene motifs and Stone-Wales transformations. As an important intermediate in the formation of high symmetry fullerene cages, the C1(51383)-C84 represents a missing link that implies the "top-down" fullerene formation mechanism. Chapter 6 describes the endeavor to functionalize two exotic EMFs, the room-temperature radical heterometallofullerene [email protected], and the egg-shaped TNT EMF [email protected] The reactivity of [email protected] is directly compared to [email protected], [email protected] and [email protected] in two reactions and the paramagnetic [email protected] is proven to be very inert toward many known common fullerene cage reactions. Eventually both EMFs have been successfully functionalized via the Bingel reaction, and the derivatives are characterized with HPLC and mass-spectrometry. Chapter 7 compares the effective… Advisors/Committee Members: Dorn, Harry C. (committeechair), Santos, Webster (committee member), Carlier, Paul R. (committee member), Gibson, Harry W. (committee member).

Subjects/Keywords: Endohedral Metallofullerene; Metal Carbide Cluster; Trimetallic Nitride Template; Clusterfullerene; "Top-down" Fullerene Formation; Isolated Pentagon Rule; Contrast Agent

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zhang, J. (2014). Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/25290

Chicago Manual of Style (16^th Edition):

Zhang, Jianyuan. “Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application.” 2014. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/25290.

MLA Handbook (7^th Edition):

Zhang, Jianyuan. “Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application.” 2014. Web. 07 Mar 2021.

Vancouver:

Zhang J. Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application. [Internet] [Doctoral dissertation]. Virginia Tech; 2014. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/25290.

Council of Science Editors:

Zhang J. Yttrium, Gadolinium, and Lutetium Based Endohedral Metallofullerenes: From Synthesis to Application. [Doctoral Dissertation]. Virginia Tech; 2014. Available from: http://hdl.handle.net/10919/25290

Virginia Tech

24. Clements, Joseph Shelby II. Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation.

Degree: PhD, Chemistry, 2017, Virginia Tech

URL: http://hdl.handle.net/10919/77918

► Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for… (more)

▼ Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. Advisors/Committee Members: Carlier, Paul R. (committeechair), Kingston, David G. I. (committee member), Tanko, James M. (committee member), Yee, Gordon T. (committee member).

Subjects/Keywords: Hydrazine; acylation; α-effect; regioselectivity; hydrazide; voltage-gated; (E)-/(Z)-; 19F NMR; single electron transfer (SET); rotational barrier; N-N bond rotation; rotational isomerism; helicity; transition state; dihedral angle

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APA (6^th Edition):

Clements, J. S. I. (2017). Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77918

Chicago Manual of Style (16^th Edition):

Clements, Joseph Shelby II. “Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation.” 2017. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77918.

MLA Handbook (7^th Edition):

Clements, Joseph Shelby II. “Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation.” 2017. Web. 07 Mar 2021.

Vancouver:

Clements JSI. Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation. [Internet] [Doctoral dissertation]. Virginia Tech; 2017. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77918.

Council of Science Editors:

Clements JSI. Synthesis of Insecticidal Mono- and Diacylhydrazines for Disruption of K+ Voltage-Gated Channels, and Elucidation of Regiochemistry and Conformational Isomerism by NMR Spectroscopy and Computation. [Doctoral Dissertation]. Virginia Tech; 2017. Available from: http://hdl.handle.net/10919/77918

Virginia Tech

25. Bryson, David Irby. Targeting RNA Structures with Multivalent Branched Peptide Libraries.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/77327

► RNA is essential for the transfer of genetic information, as the central dogma of biology dictates. The role of RNA, however, is not limited to… (more)

Subjects/Keywords: High Throughput Screening; Combinatorial Libraries; Branched Peptides; Multivalency; Cell Permeable Peptides; and Boron; RNA; HIV-1; Medium-Sized Ligands

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APA (6^th Edition):

Bryson, D. I. (2012). Targeting RNA Structures with Multivalent Branched Peptide Libraries. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/77327

Chicago Manual of Style (16^th Edition):

Bryson, David Irby. “Targeting RNA Structures with Multivalent Branched Peptide Libraries.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/77327.

MLA Handbook (7^th Edition):

Bryson, David Irby. “Targeting RNA Structures with Multivalent Branched Peptide Libraries.” 2012. Web. 07 Mar 2021.

Vancouver:

Bryson DI. Targeting RNA Structures with Multivalent Branched Peptide Libraries. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/77327.

Council of Science Editors:

Bryson DI. Targeting RNA Structures with Multivalent Branched Peptide Libraries. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/77327

Virginia Tech

26. Nelson, Amanda Kay. Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds.

Degree: PhD, Chemistry, 2016, Virginia Tech

URL: http://hdl.handle.net/10919/83400

► Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron… (more)

▼ Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron bonds and their subsequent transformations are highlighted. Among the myriad of unsaturated substrates for conducting borylation reactions, allenes have received minimal attention. These substrates are uniquely advantageous given that diboration results in the formation of both allylic and vinylic boronates. Orthogonal reactivity of the sp2 and the sp3 C-B bonds can allow for chemoselective transformations. However, oxidation of the carbon-boron bond is one example in which the conditions are unselective. To address this shortcoming, a platinum catalyst was developed for the diboration of 1,1-diaryl allenes with a differentially protected diboron reagent, pinB-Bdan. The reaction proceeds regioselectively in high yields to furnish olefins bearing a vinylic Bpin and an allylic Bdan moiety. The subsequent chemoselective transformation of each boron center was demonstrated. Methods for preparing 1,8-diaminonaphthalene protected vinylboronates conjugated to carbonyl groups are severely limited. A simple and efficient protocol was developed for carrying out an environmentally friendly copper(II)-catalyzed beta-borylation of alkynoates and alkynamides in water and open-to-air. Following the discriminative activation of the more Lewis acidic pinacol protected boron center in pinB-Bdan, a regio-, stereo- and chemoselective beta-borylation of acetylenic substrates delivers (Z)-beta-boryl enoates and primary, secondary, and tertiary enamides under very mild conditions. As an inexpensive and earth abundant metal, catalysts based on copper are highly desirable. An international collaborative project to develop a copper-catalyzed cross-coupling reaction of beta-boryl carbonyl compounds was explored. Preliminary results found these substrates to be either unstable towards or unreactive under the reactions conditions screened. Advisors/Committee Members: Santos, Webster L. (committeechair), Merola, Joseph S. (committee member), Carlier, Paul R. (committee member), Tanko, James M. (committee member).

Subjects/Keywords: borylation; diboration; conjugate addition; aqueous; copper; cross-coupling

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APA (6^th Edition):

Nelson, A. K. (2016). Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/83400

Chicago Manual of Style (16^th Edition):

Nelson, Amanda Kay. “Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds.” 2016. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/83400.

MLA Handbook (7^th Edition):

Nelson, Amanda Kay. “Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds.” 2016. Web. 07 Mar 2021.

Vancouver:

Nelson AK. Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds. [Internet] [Doctoral dissertation]. Virginia Tech; 2016. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/83400.

Council of Science Editors:

Nelson AK. Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds. [Doctoral Dissertation]. Virginia Tech; 2016. Available from: http://hdl.handle.net/10919/83400

27. Presley, Christopher Charles. Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants.

Degree: PhD, Chemistry, 2017, Virginia Tech

URL: http://hdl.handle.net/10919/79978

► As a part of the continuing search for bioactive compounds with the Madagascar International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products… (more)

Subjects/Keywords: Natural Products; Antiproliferative; Antiplasmodial; Chromane; Chromene; Crinum; Cripowellin; Quinolone; Diterpene; Triterpene

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APA (6^th Edition):

Presley, C. C. (2017). Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/79978

Chicago Manual of Style (16^th Edition):

Presley, Christopher Charles. “Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants.” 2017. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/79978.

MLA Handbook (7^th Edition):

Presley, Christopher Charles. “Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants.” 2017. Web. 07 Mar 2021.

Vancouver:

Presley CC. Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants. [Internet] [Doctoral dissertation]. Virginia Tech; 2017. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/79978.

Council of Science Editors:

Presley CC. Isolation, Structure Elucidation, and Total Synthesis of Biologically Active Natural Products from Plants. [Doctoral Dissertation]. Virginia Tech; 2017. Available from: http://hdl.handle.net/10919/79978

Virginia Tech

28. Thorpe, Steven Brandon. Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds.

Degree: PhD, Chemistry, 2012, Virginia Tech

URL: http://hdl.handle.net/10919/26669

► The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more… (more)

▼ The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the authorâ s contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents. A unique â mixedâ diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including Î±,Î²-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique Î²,Î²-diboration of an Î±,Î²-acetylenic ketone was also discovered. The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are Î±,Î²,Î³-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the Î²-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield. Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure. Advisors/Committee Members: Santos, Webster L. (committeechair), Carlier, Paul R. (committee member), Tanko, James M. (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: borylation; diboron reagent; boronic ester; conjugate addition; copper catalysis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Thorpe, S. B. (2012). Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/26669

Chicago Manual of Style (16^th Edition):

Thorpe, Steven Brandon. “Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds.” 2012. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/26669.

MLA Handbook (7^th Edition):

Thorpe, Steven Brandon. “Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds.” 2012. Web. 07 Mar 2021.

Vancouver:

Thorpe SB. Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds. [Internet] [Doctoral dissertation]. Virginia Tech; 2012. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/26669.

Council of Science Editors:

Thorpe SB. Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds. [Doctoral Dissertation]. Virginia Tech; 2012. Available from: http://hdl.handle.net/10919/26669

29. Stegall, Jeremy Brent. Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers.

Degree: PhD, Chemistry, 2014, Virginia Tech

URL: http://hdl.handle.net/10919/71291

► This dissertation describes a new platform for the synthesis of thermally reversible polymers, based on Diels-Alder reactions of bis-cyclopentadienes (bis-CPDs) and bis-maleimides (bis-MIs), that meets… (more)

▼ This dissertation describes a new platform for the synthesis of thermally reversible polymers, based on Diels-Alder reactions of bis-cyclopentadienes (bis-CPDs) and bis-maleimides (bis-MIs), that meets two main objectives. First, the bis-CPD must resist characteristic self-coupling. Second, the CPD-MI adducts should undergo the retro-Diels-Alder (rDA) reaction (i.e., thermal depolymerization) in a temperature regime that is comparable or slightly higher than that of the freely reversible bis-furan/bis-MI polymers (rDA between 80 °C and 130 °C) but much lower than that of bis-CPD homopolymers (rDA above 160 °C). Structure-reactivity relationships gleaned from the literature and from related but as yet unpublished work in our own laboratories led to our main hypothesis that a CPD moiety bearing one sterically encumbering substituent such as isopropyl (𝑖Pr) or tert-butyl (𝑡Bu) and one electronwithdrawing substituent such as perfluoroaryl would have the desired reactivity and adduct stability in combination with an 𝑁-substituted maleimide. Synthetic considerations led to a bisCPD monomer design in which two alkylcyclopentadiene groups (alkyl = 𝑖Pr or 𝑡Bu) are connected by an octafluorobiphenylene linker. As an initial fundamental step (Chapter 3), 1-(nonafluorobiphenyl-4’-yl)-4-tertbutylcyclopentadiene (1) was synthesized to provide a monofunctional model for the proposed difunctional CPD monomer. Reactions of 1 and 𝑁-(4-fluorophenyl)maleimide (FMI) afforded up to five regio- and stereo-isomeric adducts (of fourteen possible). Variable-temperature reactivity studies combined with NMR spectroscopic analysis, X-ray crystallography, and computational modeling enabled product distributions to be understood according to a conventional kinetic-vs- iii thermodynamic framework. These studies also predicted the microstructure of polymers derived from the proposed bis-CPD monomer, which is structurally analogous to 1, and bis-MIs. Moreover, 1 does not undergo DA self-coupling under ordinary conditions (T < 180 °C). Thermolysis studies of the major adducts revealed that the rDA becomes observable on a laboratory timescale (hours) at about 140 °C, which is at the upper end of the temperature range reported for furan+MI adducts but well below that of CPD+CPD adducts. In contrast, adducts formed from either of the analogous monosubstituted cyclopentadienes (𝑡BuC₅H₅ and C₆F₅C₅H₅) do not undergo rDA below 180 °C. These results strongly support the proposed bis-CPD monomer design. In a second fundamental step (Chapter 4), the hypothesis that an electron-withdrawing CPD substituent would destabilize a CPD-MI adduct was further tested by reacting 𝑁-(4- fluorophenyl)maleimide with a series of triarylated cyclopentadienes (1,2,3-Ar₃C₅H₃ and 1,2,4- Ar₃C₅H₃, Ar = C₆F₅, C₆F₄CF₃, and Ar = C₅F₄N). The perfluorophenyl- and perfluorotolylsubstituted compounds were previously reported, but the perfluoropyridyl-substituted cyclopentadienes were prepared for this study using SNAr reactions of pentafluoropyridine and sodium cyclopentadienide. The… Advisors/Committee Members: Deck, Paul A. (committeechair), Gibson, Harry W. (committee member), Madsen, Louis A. (committee member), Carlier, Paul R. (committee member).

Subjects/Keywords: Diels-Alder reaction; cyclopentadiene; maleimide; reversible; fluoroaromatic; step-growth polymer

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APA (6^th Edition):

Stegall, J. B. (2014). Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/71291

Chicago Manual of Style (16^th Edition):

Stegall, Jeremy Brent. “Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers.” 2014. Doctoral Dissertation, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/71291.

MLA Handbook (7^th Edition):

Stegall, Jeremy Brent. “Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers.” 2014. Web. 07 Mar 2021.

Vancouver:

Stegall JB. Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers. [Internet] [Doctoral dissertation]. Virginia Tech; 2014. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/71291.

Council of Science Editors:

Stegall JB. Cyclopentadiene-Maleimide Platform for Thermally Reversible Polymers. [Doctoral Dissertation]. Virginia Tech; 2014. Available from: http://hdl.handle.net/10919/71291

30. Sulier, Kiaya Minh-Li. Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases.

Degree: MS, Chemistry, 2017, Virginia Tech

URL: http://hdl.handle.net/10919/86200

► Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. PARP inhibitors (PARPi) have shown success in clinical trials for the treatment… (more)

▼ Poly-(ADP-ribsoyl) Polymerases (PARPs) are a superfamily of enzymes comprised of 17 known isoforms. PARP inhibitors (PARPi) have shown success in clinical trials for the treatment of homologous recombination-deficient cancers. Though proven effective initially, tumors treated with PARPi eventually develop resistance. Combinatorial therapeutics targeting PARP and other pathways that may re-sensitize tumors to PARP inhibition, including PI3K/AKT/mTor pathway, and cell-cycle checkpoints (such as CDKs, CHK, and Wee) are being tested. In this context, the synthetic lethality of cyclin-dependent kinase 1 (CDK1) and PARP1 is known. Evaluation of PARP1 and CDK1 pharmacophores led to the development of the tetrahydro-arylazepinone (TAAP) scaffold as a potential dual PARP1/CDK1 inhibitor. We screened a handful of TAAP analogs against PARP1 in a cell-free assay that identified the low micromolar PARP1 inhibitor 1,2,3,4-tetrahydro-5H-benzo[e][1,4]-diazepin-5-one (TBAP), which served as the lead compound. The analogous 1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]-diazepin-5-one (TPAP) series showed a similar bioactivity profile. Satisfyingly, the N1-benzyl TPAP analogue showed activity in the low nanomolar range. The TAAP series (i.e., 6/7-membered scaffold) unfortunately lacked CDK1 inhibitory activity. Finally, many PARPi's show poor isoform-selectivity. The development of isoform-selective PARPi can clarify the specific function of each PARP isoform and may reduce the adverse side effects shown by PARPi. A handful of TAAP analogs were screened against 13 PARP isoforms, where some compounds demonstrated exquisite PARP1/2 selectivity. Concurrently, we discovered an inhibitor for PARP11, an isoform that lacks any known synthetic ligand. Future directions are suggested towards fine-tuning the structure-activity relationship of TAAP-isoform selective PARPi as well as developing a dual PARP1/CDK1 inhibitor. Advisors/Committee Members: Josan, Jatinder (committeechair), Carlier, Paul R. (committee member), Merola, Joseph S. (committee member), Kingston, David G. I. (committee member).

Subjects/Keywords: Poly-(ADP-Ribosyl) Polymerase (PARP); cyclin-dependent kinase 1 (CDK1); triple negative breast cancer (TNBC); benzodiazepines; isoform specific inhibitors

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APA (6^th Edition):

Sulier, K. M. (2017). Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases. (Masters Thesis). Virginia Tech. Retrieved from http://hdl.handle.net/10919/86200

Chicago Manual of Style (16^th Edition):

Sulier, Kiaya Minh-Li. “Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases.” 2017. Masters Thesis, Virginia Tech. Accessed March 07, 2021. http://hdl.handle.net/10919/86200.

MLA Handbook (7^th Edition):

Sulier, Kiaya Minh-Li. “Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases.” 2017. Web. 07 Mar 2021.

Vancouver:

Sulier KM. Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases. [Internet] [Masters thesis]. Virginia Tech; 2017. [cited 2021 Mar 07]. Available from: http://hdl.handle.net/10919/86200.

Council of Science Editors:

Sulier KM. Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases. [Masters Thesis]. Virginia Tech; 2017. Available from: http://hdl.handle.net/10919/86200

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