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¹ The University of Texas at Austin, Austin, Texas; ² Cylene Pharmaceuticals, Inc., San Diego, California; and ³ College of Pharmacy and ⁴ Department of Chemistry, The University of Arizona and ⁵ The Arizona Cancer Center, Tucson, Arizona

Requests for reprints: Laurence H. Hurley, The Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-5622; Fax: 520-626-5623. E-mail: hurley{at}pharmacy.arizona.edu

Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O⁵-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (±)-(2'R,3'R) having the naturally occurring enantiomer (2'R,3'R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O⁵-methyl psorospermin, the order of biological potency is (2'R,3'R) > (2'R,3'S) = (2'S,3'R) > (2'S,3'S). This order of potency is also found in the topoisomerase II–induced alkylation of O⁵-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II–induced alkylation of DNA and the biological activity by psorospermin and its O⁵-methyl derivatives. Finally, (2'R,3'R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2'R,3'R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.

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.

⁶ John Cassady (Ohio State University), personal communication.

⁷ L. Hurley and I. Fellows, unpublished results.

⁸ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrgroups.org).

Received 6/ 7/05; revised 8/25/05; accepted 9/13/05.