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You searched for subject:(dibenzocyclooctadiene). Showing records 1 – 3 of 3 total matches.

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University of Saskatchewan

1. Asiamah, Isaac. Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism.

Degree: 2015, University of Saskatchewan

Nordihydroguaiaretic acid (NDGA), is a naturally-occurring lignan isolated from the creosote bush (Larrea tridentata). The aqueous extract of this shrub, commonly referred to as Chaparral tea, was listed in the American pharmacopeia as an ethnobotanical used to treat tuberculosis, arthritis and cancer. Other documented traditional applications of creosote bush extract include treatment for infertility, rheumatism, arthritis, diabetes, gallbladder and kidney stones, pain and inflammation among many others. In spite of the numerous pharmacological properties, NDGA use has been associated with toxicities including hepatotoxicity in humans. Previous studies in our group showed that oxidative cyclization of NDGA (a di-catechol) at physiological pH forms a dibenzocyclooctadiene that may have therapeutic benefits whilst oxidation to ortho-quinone likely mediates toxicological properties. In order to investigate the structural features responsible for pharmacological and toxicological properties, a series of NDGA analogues were designed, synthesized and characterized for the purpose of studying their oxidative metabolism. Literature procedures were modified to successfully prepare seven lignan analogues via multi-step synthesis. In our effort to understand the mechanisms of NDGA intramolecular cyclization, the prepared analogues were incubated under previously established conditions where NDGA autoxidized to yield the dibenzocyclooctadiene derivative. We also evaluated the stability of the analogues under the conditions of this study. Furthermore, we evaluated bioactivation potential of the prepared analogues with a goal of eliminating reactive metabolite liability through rational structural modification. We incubated NDGA and its analogues in rat liver microsomes (RLM) in the presence of glutathione as a nucleophilic trapping agent. Standards for comparison were generated by performing glutathione trapping experiments with chemical and enzyme oxidation systems. The potential of the dibenzocyclooctadiene lignan 2 derived from NDGA under physiological conditions to contribute to toxicological properties via reactive metabolite formation was also evaluated. Glutathione conjugates were detected by electrospray ionization-mass spectrometry (ESI-MS) scanning for neutral loss (NL) 129 Da or 307 Da in positive ion mode or precursor ion (PI) scanning for 272 Da in negative ion mode and further characterized by liquid chromatography–tandem mass spectrometry (LC–MS/MS) or in a single LC-MS run using multiple reactions monitoring (MRM) as a survey scan to trigger acquisition of enhanced product ion (EPI) data. We determined that NDGA autoxidation at pH 7.4 is dependent on substituents and/or substitution pattern on the two aromatic rings. In particular, spontaneous intramolecular cyclization to a dibenzocyclooctadiene required a di-catechol lignan, raising the possibility that o-Q formation may not be necessary for cyclization to occur. Cyclization was significantly inhibited in the presence of excess GSH which supports the… Advisors/Committee Members: Krol, Edward S., Remillard, Fred A., Palmer, David R., Bandy, Brian, Gravel, Michel.

Subjects/Keywords: nordihydroguaiaretic aci; lignans; dibenzocyclooctadiene; autoxidation; cyclization; bioactivation; reactive metabolites; glutathione adducts; liquid chromatography–tandem mass spectrometry (LC–MS/MS); multiple reactions monitoring (MRM); neutral loss (NL); precursor ion (PI).

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APA (6th Edition):

Asiamah, I. (2015). Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/ETD-2015-06-1915

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Asiamah, Isaac. “Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism.” 2015. Thesis, University of Saskatchewan. Accessed December 12, 2019. http://hdl.handle.net/10388/ETD-2015-06-1915.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Asiamah, Isaac. “Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism.” 2015. Web. 12 Dec 2019.

Vancouver:

Asiamah I. Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism. [Internet] [Thesis]. University of Saskatchewan; 2015. [cited 2019 Dec 12]. Available from: http://hdl.handle.net/10388/ETD-2015-06-1915.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Asiamah I. Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism. [Thesis]. University of Saskatchewan; 2015. Available from: http://hdl.handle.net/10388/ETD-2015-06-1915

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of Saskatchewan

2. Billinsky, Jennifer Lynn. Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans.

Degree: 2009, University of Saskatchewan

The rising use of natural products creates an imperative need for an enhanced awareness of the safety of current and new products making their way into the marketplace. An important example is natural products containing lignans as the principal active component. Despite their structural similarity the lignan of creosote bush can cause hepato- and renal toxicity while the lignans of flaxseed have no reported serious toxicity. This dissertation aimed to investigate the oxidative metabolism of such lignans to determine whether reversible, competitive interactions and/or bioactivation may explain the differences in their apparent toxicity. The first objective was to study the metabolism and bioactivation of nordihydroguaiaretic acid (creosote bush) and secoisolariciresinol (flaxseed). Nordihydroguaiaretic acid metabolism in rat liver microsomes led to the production of three glutathione adducts formed via ortho¬-quinone reactive intermediates. This metabolism was independent of NADPH and thus attributed to autoxidation. Secoisolariciresinol metabolism yielded lariciresinol and no glutathione adducts suggesting an absence of bioactivation to reactive quinone intermediates. The second objective was to study the autoxidation of nordihydroguaiaretic acid. The major autoxidation product was a unique, stable schisandrin-like cyclolignan which was the result of nordihydroguaiaretic acid cyclization. The half-life of nordihydroguaiaretic acid in aqueous solution, pH 7.4, 37ºC is 3.14 hours suggesting the cyclolignan may be responsible for some of the biological effects of nordihydroguaiaretic acid. The third objective was to study the inhibition of cytochrome P450 isoforms 1A2, 2B, 2C11 and 3A by lignans derived from creosote bush and flaxseed. None of the lignans caused irreversible inhibition. Both creosote bush and flaxseed lignans caused reversible inhibition of P450 enzyme activity that involved competitive or mixed-type inhibition, however the inhibition was present at nonphysiologically relevant concentrations. Activation of cytochrome P450 isoforms was also observed at low lignan concentrations. The results suggest that P450-mediated bioactivation or reversible inhibition cannot explain the differences in toxicity noted between the lignans of creosote bush and flaxseed. This work suggests a minimal risk for drug-lignan interactions at P450 enzymes. Further studies are warranted to determine the presence and biological and toxicological role of the nordihydroguaiaretic acid cyclolignan in herbal preparations. Advisors/Committee Members: Krol, Ed S., Blakley, Barry R., Alcorn, Jane, Bandy, Brian, Janz, David M., Siraki, Arno.

Subjects/Keywords: Secoisolariciresinol; Nordihydroguaiaretic acid; Flaxseed; quinone; Creosote bush; Anhydrosecoisolariciresinol; Enterolactone; Enterodiol; Dibenzocyclooctadiene; Cytochrome P450; bioactivation; inhibition; reactive intermediate; lignan; hepatotoxicity; autoxidation; Glutathione adduct

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APA (6th Edition):

Billinsky, J. L. (2009). Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/etd-09212009-165345

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Billinsky, Jennifer Lynn. “Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans.” 2009. Thesis, University of Saskatchewan. Accessed December 12, 2019. http://hdl.handle.net/10388/etd-09212009-165345.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Billinsky, Jennifer Lynn. “Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans.” 2009. Web. 12 Dec 2019.

Vancouver:

Billinsky JL. Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans. [Internet] [Thesis]. University of Saskatchewan; 2009. [cited 2019 Dec 12]. Available from: http://hdl.handle.net/10388/etd-09212009-165345.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Billinsky JL. Oxidative metabolism and cytochrome P450 enzyme inhibition potential of creosote bush and flaxseed lignans. [Thesis]. University of Saskatchewan; 2009. Available from: http://hdl.handle.net/10388/etd-09212009-165345

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

3. Gong, Wei. Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product.

Degree: PhD, Chemistry, 2012, The Ohio State University

Aiming at finding a general and broadly applicable route to dibenzocyclooctadiene(DBCOD) lignans, an important class of natural products with wide-ranging biologicalactivities, we applied Pd-catalyzed bis-metallative cyclizations mediated by a [B-Sn] reagent,1-trimethylstannyl-2,5-dimethyl-2,5-diazaborolidine, to access the core DBCOD systems. 2,2’-Dipropargyl biphenyls are suitable precursors of [B-Sn] reagent mediatedcyclizations and their acetylene moieties can be installed by addition of lithium acetylides to2’-substituted biphenyl aldehydes. Most of these acetylide additions are highlystereoselective and chelating models have been proposed to rationalize their stereochemicalresults. The viability of the [B-Sn]-mediated cyclizations of these dipropargyl biphenylsdepends on the chirality of the biphenyl scaffolding and the configuration of the propargyliccenter. Models based on steric arguments can be used to rationalize the stereochemicaloutcomes in successful cyclizations, and the reluctance in others to undergo the cyclization. A racemic synthesis of steganone was achieved from a 1,2-bisalkylidenecyclooctadieneprepared via the [B-Sn]-mediated cyclization. A novel AD-mix mediated tandem processquickly led to the formation of the key lactone, which was converted to steganone after threesteps. Eight fully substituted DBCOD lignans, including compounds such as kadsuralignan B,tiegusanin D, and schizanrin F, with a tertiary center at C7, were first synthesized using anintermediate prepared by the [B-Sn]-mediated cyclization. The unique conformations ofDBCOD intermediates are crucial for different reactivities of certain functional groups (e.g.,C-C double bonds, hydroxyl and carbonyl groups), which can explain the stereochemicaloutcome of related transformations, for example, the hydrogenation reactions, Mitsunobureactions, electrophilic additions to C-C double bonds and nucleophilic additions to carbonylgroups. The conformations of DBCODs containing C6 and/or C9 carbonyl groups are alsodiscussed based on experimental data. We provide a general approach to the syntheses ofhighly functionalized DBCOD lignan natural products (>100) and unnatural analogs withdifferent configurations and/or oxidation states at C6, C7, C8 and C9. Advisors/Committee Members: RajanBabu, thaliyil (Advisor).

Subjects/Keywords: Chemistry; dibenzocyclooctadiene (DBCOD) lignans; Multicomponent Cyclization Reactions; 2,2’ -Dipropargyl biphenyls; stereoselective acetylide additions

Dibenzocyclooctadiene (DBCOD) Natural Products via Borostannylative Cyclization of 2,2’-Dipropargyl… …Conformation and Reactivity in Dibenzocyclooctadiene Derivatives. A General Approach to Fully… …Substituted Dibenzocyclooctadiene Lignans”, Submitted. 5. Wei Gong, Ramakrishna Reddy Singidi… …Dibenzocyclooctadiene Lignans”, Chemical Science, 2012, 3, 1221-1230. 6. Wei Gong, Qianqian Li, Suyue Li… …xxxv Chapter 1. Multi-component Cyclization Reactions and Dibenzocyclooctadiene Lignans… 

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

APA (6th Edition):

Gong, W. (2012). Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1356546833

Chicago Manual of Style (16th Edition):

Gong, Wei. “Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product.” 2012. Doctoral Dissertation, The Ohio State University. Accessed December 12, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1356546833.

MLA Handbook (7th Edition):

Gong, Wei. “Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product.” 2012. Web. 12 Dec 2019.

Vancouver:

Gong W. Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product. [Internet] [Doctoral dissertation]. The Ohio State University; 2012. [cited 2019 Dec 12]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1356546833.

Council of Science Editors:

Gong W. Multicomponent Cyclization Reactions: A General Approach To Dibenzocyclooctadiene Lignan Natural Product. [Doctoral Dissertation]. The Ohio State University; 2012. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1356546833

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