Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.
Targeting the microtubule system represents an attractive strategy for the development of anticancer agents. In this study, we report a class of combretastatin A-4 (CA-4) analogs derivatized with a boronic acid moiety replacing the hydroxyl group on the C-ring of CA-4. Docking studies of the X-ray structures of our aryl-boronic analogs onto an X-ray structure of the alpha,beta-tubulin heterodimer suggested that cis-6 was a potent inhibitor of the colchicine binding. The model indicated that there would be strong hydrogen bonding between the boronic acid moiety and Thr-179 and Val-181 of alpha-tubulin. We demonstrate that the cis-6 boronic acid bioisostere of CA-4: (1) inhibits tubulin assembly, (2) competitively displaces colchicine, and (3) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4.
Kong
Yali
Y
Department of Chemistry, University of Virginia, Charlottesville, 22904, USA.
Grembecka
Jolanta
J
Edler
Michael C
MC
Hamel
Ernest
E
Mooberry
Susan L
SL
Sabat
Michal
M
Rieger
Jayson
J
Brown
Milton L
ML
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D013267:Stilbenes; C058728:fosbretabulin