A boronic acid chalcone analog of combretastatin A-4 as a potent anti-proliferation agent.
Chalcones represent a class of natural products that inhibits tubulin assembly. In this study we designed and synthesized boronic acid analogs of chalcones in an effort to compare biological activities with combretastatin A-4, a potent inhibitor of tubulin polymerization. Systematic evaluation of the positional effects of the carbonyl moiety towards inhibition of tubulin polymerization, cancer cell proliferation and angiogenesis revealed that placement of the carbonyl adjacent to the trimethoxybenzene A-ring resulted in more active compounds than when the carbonyl group was placed adjacent to the C-ring. Our study identified a boronic acid chalcone with inhibition towards 16 human cancer cell lines in the 10-200nM range, and another three cell lines with GI(50)-values below 10nM. Furthermore, this drug has significant anti-angiogenesis effects demonstrated by HUVEC tube formation and aortic ring assay.
Kong
Yali
Y
Department of Oncology, 3970 Reservoir Road, Drug Discovery Program, Georgetown University Medical Center, Washington, DC 20057, United States.
Wang
Kan
K
Edler
Michael C
MC
Hamel
Ernest
E
Mooberry
Susan L
SL
Paige
Mikell A
MA
Brown
Milton L
ML
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001897:Boronic Acids; D013267:Stilbenes; D002599:Chalcone; C058728:fosbretabulin