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Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties

  1. Author:
    Flynn, B. L.
    Gill, G. S.
    Grobelny, D. W.
    Chaplin, J. H.
    Paul, D.
    Leske, A. F.
    Lavranos, T. C.
    Chalmers, D. K.
    Charman, S. A.
    Kostewicz, E.
    Shackleford, D. M.
    Morizzi, J.
    Hamel, E.
    Jung, M. K.
    Kremmidiotis, G.

  2. Author Address

    [Flynn, BL; Gill, GS; Grobelny, DW; Chaplin, JH; Paul, D; Leske, AF; Lavranos, TC; Kremmidiotis, G] Bionomics Ltd, Thebarton, SA 5031, Australia. [Charman, SA; Kostewicz, E; Shackleford, DM; Morizzi, J] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia. [Hamel, E] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Jung, MK] NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD 20892 USA.;Flynn, BL (reprint author), Bionomics Ltd, 31 Dalgleish St, Thebarton, SA 5031, Australia;bernard.flynn@monash.edu
    1. Year: 2011
    2. Date: Sep
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 17
    3. Pages: 6014-6027
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    A structure activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo-[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).

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External Sources

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  2. DOI: 10.1021/jm200454y
  3. View record in Web of Science®
  4. WOS: 000294385700005

Library Notes

  1. Fiscal Year: FY2011-2012
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