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

Abstract

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.

• Authors: Ingrid M Fellows, Michael Schwaebe, Thomas S Dexheimer, Hariprasad Vankayalapati, Mary Gleason-Guzman, Jeffrey P Whitten, Laurence H Hurley
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 4 Issue 11 Pg. 1729-39 (Nov 2005) ISSN: 1535-7163 [Print] United States
• PMID: 16275994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Epoxy Compounds
• Xanthones
• Deoxycytidine
• psorospermin
• DNA
• DNA Topoisomerases, Type II
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Body Weight
• Cell Line
• Cell Line, Tumor
• DNA (chemistry)
• DNA Topoisomerases, Type II (metabolism)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
• 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, enzymology, pathology)
• Stereoisomerism
• Time Factors
• Xanthones (administration & dosage, chemical synthesis, chemistry)
• Gemcitabine