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You searched for subject:(Bifunctional inhibitors). Showing records 1 – 2 of 2 total matches.

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1. Patil, Vishal. Design and synthesis of small molecule inhibitors of zinc metalloenzymes.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

Histone deacetylases (HDACs) are a class of enzymes that play a crucial role in DNA expression by removing an acetyl group from the Ι›-N-acetyl lysine residue on histone proteins. Out of 18 isoforms of HDAC enzymes which are classified into 4 classes, only 11 of them are metalloenzymes that require zinc for its catalytic activity. HDACs are considered promising target for drug development in cancer and other parasitic diseases due to their role in gene expression. Histone deacetylase inhibitors (HDACi) can cause cell cycle arrest, and induce differentiation or apotosis. While HDACi shows promising antitumor effects, their mechanism of action and selectivity against cancer cells have not been adequately defined yet. In addition, low oral bioavailability, short half-life time, bone marrow toxicity, and cardiotoxicity limit their use in clinic. Therefore, there is considerable interest in developing compounds with selectivity and specificity towards individual family members of HDACs. The prototypical pharmacophore for HDAC inhibitors consist of a metal-binding moiety that coordinates to the catalytic metal ion within the HDAC active site, a capping group that interacts with the residues at the entrance of the active site and a linker that appropriately positions the metal-binding moiety and capping group for interactions in the active site. It has been shown that modification of cap, cap linking moiety, linker or zinc binding group (ZBG) shows promises of superior potency and isoform selectivity. My thesis research involves manipulating different aspects of the pharmacophoric model to yield not only more potent, selective, and effective drugs but also to help understand the biology of HDAC isoforms. In addition, I was successful in extending studies on HDAC isoforms to other zinc metalloenzymes such as leishmanolysin (gp63) and spliceosome associated zinc-metalloenzymes to understand biology of these zinc metalloenzymes by developing potent and selective small molecule inhibitors. This will aid in improvement of existing therapeutics for treatment of cancer, leishmania, malaria and other genetic disorders. Advisors/Committee Members: Oyelere, Adegboyega (Committee Chair), France, Stefan (Committee Member), Murthy, Niren (Committee Member), Powers, James (Committee Member), Tolbert, Laren (Committee Member).

Subjects/Keywords: Bifunctional inhibitors; Isoform selectivity; Spliceosome assembly inhibitors; Leishmania; Malaria; Histone deacetylase inhibitors; Cancer chemotherapy; Zinc binding groups; Metalloenzymes; Enzymes; Metalloproteins

…1.4 Bifunctional Inhibitors Currently a β€œone drug, one target” paradigm is the dominant… …Generation GP63 Inhibitors by Molecular Docking Analysis €¦β€¦.233 6.5 Whole Cell Activities of 1st… …inhibition activity of novel HDAC/Topo I inhibitors...114 Table 5-1 3-HPT fragment activities… …Representative topoisomerase I inhibitors €¦ €¦ €¦ €¦ €¦..13 Figure 1-9 Steps involved in splicing… …Design of dual-acting Topo II-HDAC inhibitors €¦ €¦β€¦..….100 Figure 4-4 Synthesis of the SAHA… 

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APA (6th Edition):

Patil, V. (2011). Design and synthesis of small molecule inhibitors of zinc metalloenzymes. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/45859

Chicago Manual of Style (16th Edition):

Patil, Vishal. “Design and synthesis of small molecule inhibitors of zinc metalloenzymes.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 22, 2021. http://hdl.handle.net/1853/45859.

MLA Handbook (7th Edition):

Patil, Vishal. “Design and synthesis of small molecule inhibitors of zinc metalloenzymes.” 2011. Web. 22 Jan 2021.

Vancouver:

Patil V. Design and synthesis of small molecule inhibitors of zinc metalloenzymes. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1853/45859.

Council of Science Editors:

Patil V. Design and synthesis of small molecule inhibitors of zinc metalloenzymes. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/45859

2. Guerrant, William. Targeted histone deacetylase inhibition.

Degree: PhD, Chemistry and Biochemistry, 2012, Georgia Tech

Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo. Advisors/Committee Members: Yomi Oyelere (Committee Chair), Donald Doyle (Committee Member), James Powers (Committee Member), Loren Williams (Committee Member), Yuhong Fan (Committee Member).

Subjects/Keywords: HDAC inhibitors; Drug design; Targeted drug delivery; HDAC; Histone deacetylase; Bifunctional inhibitors; Cancer therapy; Drug delivery systems; Cancer Treatment; Enzymes

…of Radiolabeled Macrocyclic HDAC Inhibitors 125 4.5 Conclusion 131 4.6 Experimental 134… …Topo II-HDAC inhibitors. 58 Figure 3-3: Docked structures of Topo II-HDACi conjugates at… …II inhibition. 72 Figure 3-9: Intracellular distribution of dual-acting inhibitors in DU… …145 cells. 74 Figure 3-10: Intracellular distribution of dual-acting inhibitors in A549… …lung cancer cells. 74 Figure 3-11: Representative structures of camptothecin inhibitors of… 

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

APA (6th Edition):

Guerrant, W. (2012). Targeted histone deacetylase inhibition. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/44907

Chicago Manual of Style (16th Edition):

Guerrant, William. “Targeted histone deacetylase inhibition.” 2012. Doctoral Dissertation, Georgia Tech. Accessed January 22, 2021. http://hdl.handle.net/1853/44907.

MLA Handbook (7th Edition):

Guerrant, William. “Targeted histone deacetylase inhibition.” 2012. Web. 22 Jan 2021.

Vancouver:

Guerrant W. Targeted histone deacetylase inhibition. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1853/44907.

Council of Science Editors:

Guerrant W. Targeted histone deacetylase inhibition. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/44907

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