Function-oriented synthesis: Biological evaluation of laulimalide analogues derived from a last step cross metathesis diversification strategy

Susan L. Mooberry, Michael K. Hilinski, Erin A. Clark, Paul A. Wender

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis diversification strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 μM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C23-C27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more than a bystander role.

Original languageEnglish (US)
Pages (from-to)829-838
Number of pages10
JournalMolecular Pharmaceutics
Volume5
Issue number5
DOIs
Publication statusPublished - Sep 1 2008

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Keywords

  • Antimitotics
  • Laulimalide
  • Laulimalide analogues
  • Metathesis
  • Microtubule stabilizers
  • Synthetic chemistry

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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