First total synthesis of stipiamide and related polyenes for the reversal of multidrug resistance
Abstract
Stipiamide has recently been shown to partially reverse multidrug resistance (MDR), a condition common to many cancer cell lines often rendering tumors unstoppable. In order to develop more useful MDR-inhibitors, a flexible synthetic approach to stipiamide was found. Methodologies developed during this synthesis include: a novel higher-order tributylstannyl cuprate-acetylene-alkynyl ester tandem addition reaction to give vinyltin diene ester 17 and a selective olefin dihydroxylation of non-conjugated dienes in favor of the terminal olefin to give diol 6. Another highlight of this synthetic sequence is the use of a Stille coupling as the concluding reaction in the formation of the challenging (E,E,Z,E,E)-pentaene array. This efficient approach tolerates sensitive functionality and demonstrated the appropriateness of the Stille coupling for the construction of the extended polyene system. Utilizing advanced intermediate 16 of the stipiamide route, dehydro-stipiamide 21 was constructed and tested for its MDR-inhibition capabilities in human MCF-7 adriamycin resistant breast cancer cells. Dehydro-stipiamide 21, which varied from stipiamide only by the substitution of a triple bond for the Z-olefin, showed a marked improvement in MDR inhibition in vitro and proved less toxic than stipiamide by a factor of ten thousand! Several simplified enyne variants were then designed and synthesized in order to further improve their ability to reverse MDR. A dramatic improvement was seen in the case of enyne 40 which can fully reverse MDR at 29% of its ED$\sb{50}$ making it superior to verapamil, the current clinical standard. Problems with the vinyl iodide/alkyne coupling (Sonogashira reaction) were also investigated leading to an increase in the yields of simplified enynes 38, 39, and 40.
Degree
Ph.D.
Advisors
Andrus, Purdue University.
Subject Area
Organic chemistry|Pharmacology
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