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Structure-based discovery of a boronic acid bioisostere of combretastatin A-4

  1. Author:
    Kong, Y.
    Grembecka, J.
    Edler, M. C.
    Hamel, E.
    Mooberry, S. L.
    Sabat, M.
    Rieger, J.
    Brown, M. L.

  2. Author Address

    Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. Univ Virginia, Charlottesville, VA 22908 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Screening Technol Branch,NIH, Frederick, MD 21702 USA. SW Fdn Biomed Res, Dept Physiol & Med, San Antonio, TX 78245 USA Brown, ML, Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA
    1. Year: 2005
    2. Date: SEP
  2. Journal: Chemistry & Biology
    1. 12
    2. 9
    3. Pages: 1007-1014
  4. Type of Article: Article
  1. 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 arylboronic analogs onto an X-ray structure of the a, 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-1 79 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 (13) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4

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External Sources

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  2. DOI: 10.1016/j.chembiol.2005.06.016
  3. View record in Web of Science®
  4. WOS: 000232361000011

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