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

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 GI 50=4.07×10 −8 M) and potent inhibition of tubulin polymerization (IC 50=1.4±0.1 μM). The 4′-azido analogue 5 has lower activity (NCI 60 cell line panel, average GI 50=2.28×10 −6 M, and IC 50=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.