Synthesis and biological evaluation of aryl azide derivatives of combretastatin a-4 as molecular probes for tubulin

Kevin G. Pinney, Maria P. Mejia, Victor M. Villalobos, Brent E. Rosenquist, George Pettit, Pascal Verdier-Pinard, Ernest Hamel

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Two new aryl azides, (Z)-1-(3'-azido-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 9 and (Z)-1-(4'-azido-3'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 5, modeled after the potent antitumor, antimitotic agent combretastatin A-4 (CA-4), have been prepared by chemical synthesis as potentially useful photoaffinity labeling reagents for the colchicine site on β-tubulin. Aryl azide 9, in which the 3'-hydroxyl group of CA-4 is replaced by an azido moiety, demonstrates excellent in vitro cytotoxicity against human cancer cell lines (NCI 60 cell line panel, average GI50=4.07x10-8 M) and potent inhibition of tubulin polymerization (IC50=1.4±0.1 μM). The 4'-azido analogue 5 has lower activity (NCI 60 cell line panel, average GI50=2.28x10-6 M, and IC50=5.2 ±0.2 μM for inhibition of tubulin polymerization), suggesting the importance of the 4'-methoxy moiety for interaction with the colchicine binding site on tubulin. These CA-4 aryl azide analogues also inhibit binding of colchicine to tubulin, as does the parent CA-4, and therefore these compounds are excellent candidates for photoaffinity labeling studies. Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2417-2425
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number10
DOIs
StatePublished - Oct 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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