Library Synthesis Of Piperidinone Sulfonamides, Transition Metal-Free C-H Trifluoromethylation Of Cyclic Enaminones, And Elucidating The Binding Site Of Epothilones On Beta-Tubulin With Epothilone Photoaffinity Probes
2014-07
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Library Synthesis Of Piperidinone Sulfonamides, Transition Metal-Free C-H Trifluoromethylation Of Cyclic Enaminones, And Elucidating The Binding Site Of Epothilones On Beta-Tubulin With Epothilone Photoaffinity Probes
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2014-07
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Chapter 1 focuses on synthesizing a library of piperidinone sulfonamides. The piperidinones serve as valuables intermediates for the synthesis of nitrogen-containing bioactive molecules, various alkaloids, and drug candidates. Amongst the myriads of highly derivatized N-heterocyclic compounds, molecules possessing the piperidinone sulfonamide moiety in their structures show interesting biological activities. A library of 18 piperidinone sulfonamides was prepared under a Pilot Scale Library grant and submitted to NIH for testing in various biological assays. Two compounds from the library were identified as active hits. One of the compounds showed prion protein 5' UTR inhibition while the other showed inhibition of human platelet-activating factor acetylhydrolase 1b, catalytic subunit 2. Chapter 2 focuses on direct C-H trifluoromethylation of cyclic enaminones. Cyclic enaminones are of interest in natural product synthesis and are regarded as valuable synthons due to unique structural and chemical properties. They serve as versatile precursors for synthesizing piperidine-containing alkaloids and drug molecules. In this project, transition metal free, direct C-H trifluoromethylation of cyclic enaminones was developed with trimethyl(trifluoromethyl)silane (TMSCF3). This method proceeds under mild conditions at room temperature and possibly involves a radical mechanism. The C-H functionalization was successful with both electron-rich and electron-deficient cyclic enaminones. This methodology circumvents substrate prefunctionalization and transition metal catalysis, and allows a convenient and direct access to a variety of medicinally significant 3-trifluoromethylpiperidine derivatives. This chemistry also presents a rare example of a direct trifluoromethylation of an internal olefinic C-H bond. Chapter 3 focuses on efforts toward elucidating the binding site of epothilones on ß-tubulin. Epothilones are potent cytotoxic tubulin-binding polyketide-derived macrolides. Even though the binding sites for epothilones and paclitaxel on ß-tubulin overlap, epothilones show efficacy against paclitaxel-resistant cancer cell lines. This implies a significantly different binding mode for epothilones. To date, two epothilone binding models have been proposed based on NMR and electron-crystallography data. In order to differentiate the proposed binding modes, four epothilone A photoaffinity analogues were designed. Three of those analogues were successfully synthesized and showed excellent cytotoxicity as well as the required tubulin assembly. It was hypothesized that the protein region labeled by these photoprobes is dependent on the epothilone conformation at the binding site. For one of the analogues, the probe-labeled peptide fragment `TARGSQQY' (residues 274 to 281) in the ß-tubulin isoform TBB3 was identified by MS analysis. Our experimental results corroborated the consensus of both the models that Thr 274 and Arg 276 are necessary for binding of epothilones to ß-tubulin. However, based on the photoaffinity labeling studies results and molecular modeling studies, an orientation of the epothilone in the binding site is proposed that is significantly different from those previously proposed.
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University of Minnesota Ph.D. dissertation.July 2014. Major: Medicinal Chemistry. Advisor: Gunda Georg. 1 computer file (PDF); xxii, 198 pages.
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Ranade, Adwait. (2014). Library Synthesis Of Piperidinone Sulfonamides, Transition Metal-Free C-H Trifluoromethylation Of Cyclic Enaminones, And Elucidating The Binding Site Of Epothilones On Beta-Tubulin With Epothilone Photoaffinity Probes. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/191462.
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