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Regioselective Synthesis of Water-Soluble Monophosphate Derivatives of Combretastatin A-1

  1. Author:
    Tanpure, R. P.
    Nguyen, B. L.
    Strecker, T. E.
    Aguirre, S.
    Sharma, S.
    Chaplin, D. J.
    Siim, B. G.
    Hamel, E.
    Lippert, J. W.
    Pettit, G. R.
    Trawick, M. L.
    Pinney, K. G.

  2. Author Address

    [Tanpure, RP; Nguyen, BL; Strecker, TE; Aguirre, S; Trawick, ML; Pinney, KG] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA [Sharma, S; Chaplin, DJ; Siim, BG] OXiGENE Inc, San Francisco, CA 94080 USA [Hamel, E] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA [Pettit, GR] Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA [Pettit, GR] Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA;Pinney, KG (reprint author), Baylor Univ, Dept Chem & Biochem, 1 Bear Pl 97348, Waco, TX 76798 USA;Kevin_Pinney@baylor.edu
    1. Year: 2011
    2. Date: Jul
  2. Journal: Journal of Natural Products
    1. 74
    2. 7
    3. Pages: 1568-1574
  4. Type of Article: Article
  5. ISSN: 0163-3864
  1. Abstract:

    The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC(50) = 1-2 mu M). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regio chemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (Ic(50) > 40 mu M), as anticipated in this pure protein assay.

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  2. DOI: 10.1021/np200104t
  3. View record in Web of Science®
  4. WOS: 000293036100003

Library Notes

  1. Fiscal Year: FY2010-2011
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