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

Mol Pharm. Sep-Oct 2008;5(5):829-38. doi: 10.1021/mp800043n. Epub 2008 Jul 29.

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 muM, 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 C 23-C 27 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Flow Cytometry
  • Humans
  • Inhibitory Concentration 50
  • Macrolides / chemistry*
  • Macrolides / pharmacology
  • Microtubules / drug effects
  • Molecular Structure
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Spindle Apparatus / drug effects
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Macrolides
  • Proto-Oncogene Proteins c-bcl-2
  • laulimalide