Design and synthesis of tubulysin analogs that stabilize and mimic a key acetate important for potent antiproliferative activity against multi-drug resistant cancers
2012-10
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Design and synthesis of tubulysin analogs that stabilize and mimic a key acetate important for potent antiproliferative activity against multi-drug resistant cancers
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2012-10
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Tubulysins are antimitotic natural products with potent anticancer activity against multidrug-resistant (MDR) cancer cells, acting by inhibition of tubulin polymerization. The marked difference in antiproliferative activity between tubulysins V and U exemplifies the importance of an acetate positioned alpha to the thiazole ring. However, this acetate has been shown to be labile under both acidic and basic conditions, so the effectiveness of this modification may be hindered due to this instability. Hence, the work presented here focuses on the synthesis of analogs that mimic and stabilize the acetate at this position.Heteroatom exchange at the α-thiazole position of tubuvaline was hypothesized to increase molecular stability while maintaining observed activity by bioisosteric replacement of the tubuvaline oxygen with a nitrogen. The nitrogen-containing analogs of tubulysin V and U, <italic><super>N </super> </italic>tubulysin V and U, were the most important targets to test the singular modification of heteroatom exchange on bioactivity and to survey molecular stability. The synthetically derived <italic><super>N </super> </italic>tubuvaline amino acid residue was generated following a rigorously controlled Mitsunobu reaction, but difficult final stage deprotections to <italic><super>N </super> </italic>tubulysin V suggests a lowered stability compared to tubulysin V. <italic>N</italic>-acylation of a penultimate tetrapeptide intermediate led to generation of <italic><super>N </super> </italic>tubulysin U and other acylated <italic><super>N </super> </italic>tubulysin analogs to establish a more robust SAR at the α-thiazole position. <italic><super>N </super> </italic>Tubulysin U was found to be more stable than tubulysin U under strongly basic conditions, and upcoming biochemical evaluation will determine the effect that these modifications have on antiproliferative activity.Investigations into the SAR at the tubuvaline α-thiazole position also included oxygen-based analogs, where two methods for acylation of tubulysin V were exploited to generate <italic>O</italic>-acylated analogs with various alkyl groups. Biochemical evaluation of antiproliferative activity, along with the use of two electrophilic analogs to act as affinity labels, will survey important interactions within the tubulysin-tubulin binding site.
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University of Minnesota Ph.D. dissertation. October 2012. Major: Medicinal Chemistry. Advisor: Robert Andrew Fecik. 1 computer file (PDF); xi, 217 pages.
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Peterson, Michael Thomas. (2012). Design and synthesis of tubulysin analogs that stabilize and mimic a key acetate important for potent antiproliferative activity against multi-drug resistant cancers. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/168283.
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