TY - JOUR
T1 - Synthesis and biological evaluation of aryl azide derivatives of combretastatin a-4 as molecular probes for tubulin
AU - Pinney, Kevin G.
AU - Mejia, Maria P.
AU - Villalobos, Victor M.
AU - Rosenquist, Brent E.
AU - Pettit, George
AU - Verdier-Pinard, Pascal
AU - Hamel, Ernest
N1 - Funding Information:
K.G.P. thanks The Robert A. Welch Foundation (Grant No. AA-1278), Baylor University, and Baylor University Research Committee for financial support of this project. G.R.P. thanks The Arizona Disease Control Research Commission, Outstanding Investigator Grant CA-44344-06-11 awarded by the DCTD, National Cancer Institute, DHHS, Drs. J.-C. Chapuis, F. Hogan, and J. M. Schmidt.
PY - 2000/10
Y1 - 2000/10
N2 - 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.
AB - 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.
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U2 - 10.1016/S0968-0896(00)00176-0
DO - 10.1016/S0968-0896(00)00176-0
M3 - Article
C2 - 11058036
AN - SCOPUS:0033811815
SN - 0968-0896
VL - 8
SP - 2417
EP - 2425
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 10
ER -