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 GI50 = 4.07 x 10(-8) M) and potent inhibition of tubulin polymerization (IC50 = 1.4+/-0.1 microM). The 4'-azido analogue 5 has lower activity (NCI 60 cell line panel, average GI50 = 2.28 x 10(-6) M, and IC50 = 5.2+/-0.2 microM 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.
Pinney
K G
KG
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA. kevin_pinney@baylor.edu
Mejia
M P
MP
Villalobos
V M
VM
Rosenquist
B E
BE
Pettit
G R
GR
Verdier-Pinard
P
P
Hamel
E
E
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001386:Azides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008961:Models, Structural; D015335:Molecular Probes; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D013696:Temperature; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D001386:Azides; D015335:Molecular Probes; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin