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¹ Maxim Pharmaceuticals, Inc., San Diego, California and ² Shire BioChem, Inc., Laval, Quebec, Canada

Requests for reprints: Shailaja Kasibhatla, Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121. Phone: 858-202-4042; Fax: 858-202-4000. E-mail: skasibhatla{at}maxim.com

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC₅₀ of 50 nmol/L and inhibited cell growth with a GI₅₀ of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G₂-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI₅₀ value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S. Kasibhatla and H. Gourdeau contributed equally to this work.

³ W. Kemnitzer et al. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay; structure-activity relationships of the 4-aryl group. J Med Chem. In Press 2004.

Received 5/ 7/04; revised 7/16/04; accepted 9/15/04.

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