Title:
Design and synthesis of small molecule inhibitors of zinc metalloenzymes

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dc.contributor.advisor Oyelere, Adegboyega K.
dc.contributor.author Patil, Vishal en_US
dc.contributor.committeeMember France, Stefan
dc.contributor.committeeMember Murthy, Niren
dc.contributor.committeeMember Powers, James
dc.contributor.committeeMember Tolbert, Laren
dc.contributor.department Chemistry and Biochemistry en_US
dc.date.accessioned 2013-01-17T21:51:27Z
dc.date.available 2013-01-17T21:51:27Z
dc.date.issued 2011-10-28 en_US
dc.description.abstract Histone deacetylases (HDACs) are a class of enzymes that play a crucial role in DNA expression by removing an acetyl group from the ɛ-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. en_US
dc.description.degree PhD en_US
dc.identifier.uri http://hdl.handle.net/1853/45859
dc.publisher Georgia Institute of Technology en_US
dc.subject Bifunctional inhibitors en_US
dc.subject Isoform selectivity en_US
dc.subject Spliceosome assembly inhibitors en_US
dc.subject Leishmania en_US
dc.subject Malaria en_US
dc.subject Histone deacetylase inhibitors en_US
dc.subject Cancer chemotherapy en_US
dc.subject Zinc binding groups en_US
dc.subject.lcsh Metalloenzymes
dc.subject.lcsh Enzymes
dc.subject.lcsh Metalloproteins
dc.title Design and synthesis of small molecule inhibitors of zinc metalloenzymes en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Oyelere, Adegboyega K.
local.contributor.corporatename School of Chemistry and Biochemistry
local.contributor.corporatename College of Sciences
relation.isAdvisorOfPublication 559ad46f-fbf0-4834-aed9-4c606a8e0790
relation.isOrgUnitOfPublication f1725b93-3ab8-4c47-a4c3-3596c03d6f1e
relation.isOrgUnitOfPublication 85042be6-2d68-4e07-b384-e1f908fae48a
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