Synthetic reactions with rare taccalonolides reveal the value of C-22,23 epoxidation for microtubule stabilizing potency

Jiangnan Peng, April L. Risinger, Jing Li, Susan L. Mooberry

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC50 values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers.

Original languageEnglish (US)
Pages (from-to)6141-6149
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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