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dc.contributor.authorShen, Kui
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 62-06, Section: B, page: 2706.;Advisors: David S. Lawrence.
dc.description.abstractProtein tyrosine phosphatase 1B (PTP1B) has been clearly implicated as a negative regulator of insulin signaling and its overexpression or high activity has been closely associated with human diseases such as diabetes and cancers. Therefore potent and selective inhibitors of PTP1B are highly desirable both as pharmacological tools in biological studies and potential therapeutics for treatment of these diseases.;Previous studies showed that PTP1B has two binding sites for phenylphosphates, one the canonical catalytic site, the other a noncatalytic site and that the noncatalytic site is located in the nonconserved region of protein tyrosine phosphatases. In addition, the peptides with acidic residues N-terminal to pTyr are preferred as PTP1B substrates. So highly selective inhibitors with high affinity for this enzyme might be obtained if the binding affinity at the two or more sites is utilized simultaneously.;On the basis of the above hypothesis, I first obtained highly selective PTP1B inhibitors with Ki values in the low micromolar range through traditional multistep synthesis of a series of bis- and tris-phenyldifluorophosphates. Then by combining a PTP1B inactive substrate-trapping mutant-based enzyme-linked immunosorbent assay (ELISA) with combinatorial/parallel synthesis, I identified a high-affinity lead substrate, and therefore by subsequent conversion into nonhydrolytic difluorophosphonates, a highly potent and specific PTP1B inhibitor with the highest-ever potency, a Ki in the low nanomolar range.
dc.publisherProQuest Dissertations & Theses
dc.subjectOrganic chemistry.
dc.titleDesign and synthesis of small molecule inhibitors of protein tyrosine phosphatase 1B

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