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

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 beta-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 GI(50) = 4.07x10(-8) M) and potent inhibition of tubulin polymerization (IC50 = 1.4+/-0.1 mu M). The 4'-azido analogue 5 has lower activity (NCI 60 cell line panel, average GI(50) = 2.28x10(-6) M, and IC50= 5.2 +/-0.2 mu M 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. (C) 2000 Elsevier Science Ltd. All rights reserved.

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