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

Bernard Flynn, Gurmit Gill, Damian Grobelny, Jason Chaplin, Dharam Paul, Annabell Leske, Tina Lavranos, David Chalmers, Susan Charman, Edmund Kostewicz, David Shackleford, Julia Morizzi, Ernest Hamel, M Jung, Gabriel Kremmidiotis

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    116 Citations (Scopus)

    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).

    Original languageEnglish
    Pages (from-to)6014-6027
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Volume54
    Issue number17
    DOIs
    Publication statusPublished - 8 Sep 2011

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