Taccalonolide C-6 Analogues, including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities

April L. Risinger, Shayne D. Hastings, Lin Du

Research output: Contribution to journalReview articlepeer-review

Abstract

The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-Tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 N-Acyl-β-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy taccalonolide AJ. Covalent docking demonstrated that the C-13 paclitaxel side chain occupied a binding pocket adjacent to the core taccalonolide pocket near the M-loop of β-Tubulin. Although paclitaxel-Taccalonolide hybrids demonstrated improved in vitro biochemical potency, they retained features of the taccalonolide chemotype, including a lag in tubulin polymerization and high degree of cellular persistence after drug washout associated with covalent binding. Together, these data demonstrate that C-6 modifications can improve the target engagement of this covalent class of microtubule drugs without substantively changing their mechanism of action.

Original languageEnglish (US)
Pages (from-to)1799-1805
Number of pages7
JournalJournal of Natural Products
Volume84
Issue number6
DOIs
StatePublished - Jun 25 2021

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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