Determination of the importance of the stereochemistry of psorospermin in topoisomerase II–induced alkylation of DNA and in vitro and in vivo biological activity

• Published in: Molecular cancer therapeutics Vol. 4; no. 11; pp. 1729 - 1739
• Main Authors: Fellows, Ingrid M, Schwaebe, Michael, Dexheimer, Thomas S, Vankayalapati, Hariprasad, Gleason-Guzman, Mary, Whitten, Jeffrey P, Hurley, Laurence H
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.11.2005
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line; Cell Line, Tumor; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; DNA - chemistry; DNA Topoisomerases, Type II - metabolism; drug resistance; Drug Screening Assays, Antitumor; Epoxy Compounds - chemistry; In Vitro Techniques; Inhibitory Concentration 50; Leukemia - drug therapy; Lymphoma - drug therapy; Mice; Mice, Nude; Models, Chemical; Models, Molecular; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - pathology; psorospermin; stereochemistry; Stereoisomerism; Time Factors; Xanthones - administration & dosage; Xanthones - chemical synthesis; Xanthones - chemistry
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-05-0183

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 O 5 -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 O 5 -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 O 5 -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 O 5 -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.