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Research Articles

Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities

¹ Dartmouth Medical School; ² Dartmouth College, Hanover, New Hampshire; ³ Rutgers, The State University of New Jersey, Piscataway, New Jersey; and ⁴ The Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-6558; Fax: 603-650-1129. E-mail: Michael.Sporn{at}dartmouth.edu

Abstract

Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak^–/– fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies. [Mol Cancer Ther 2007;6(7):2113–9]

Grant support: National Foundation for Cancer Research and NIH grant RO1 CA78814 (M. B. Sporn). We also thank the members of the Dartmouth College Class of 1934, Reata Pharmaceuticals, Inc., and the National Foundation for Cancer Research for continuing support.

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: K. Liby and T. Honda are co-first authors and contributed equally to this work. Preliminary results from this investigation were presented at the 97th Annual Meeting of the American Association for Cancer Research in Washington, DC in 2006.

Received 3/13/07; revised 4/27/07; accepted 5/21/07.