Identification of C-6 as a New Site for Linker Conjugation to the Taccalonolide Microtubule Stabilizers

Lin Du, April L. Risinger, Samantha S. Yee, Antonius R.B. Ola, Cynthia L. Zammiello, Robert H. Cichewicz, Susan L. Mooberry

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The taccalonolides are a class of microtubule stabilizers that circumvent clinically relevant forms of drug resistance due to their unique mechanism of microtubule stabilization imparted by the covalent binding of the C-22-C-23 epoxide moiety to tubulin. A taccalonolide (8) with a fluorescein group attached with a linker at C-6 was generated, and biochemical and cell-based assays showed that it bound directly to tubulin and stabilized microtubules. This pharmacological probe has allowed, for the first time, a direct visualization of a taccalonolide binding to microtubules, verifying their cellular binding site. This C-6-modified taccalonolide showed potency comparable to the untagged compound in biochemical experiments; however, its potency was lower in cellular assays, presumably due to decreased cellular permeability. These studies provide a valuable tool to facilitate the further understanding of taccalonolide pharmacology and demonstrate that C-6 is a promising site for a linker to be added to this novel class of microtubule stabilizers for targeted drug delivery.

Original languageEnglish (US)
Pages (from-to)583-588
Number of pages6
JournalJournal of Natural Products
Volume82
Issue number3
DOIs
StatePublished - Mar 22 2019

ASJC Scopus subject areas

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

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