title: Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, 22904, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Michael C
authors.initials: MC
authors.lastname: Edler
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Michal
authors.initials: M
authors.lastname: Sabat
authors.forename: Jayson
authors.initials: J
authors.lastname: Rieger
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: 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
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D013267:Stilbenes; C058728:fosbretabulin