Determination of the importance of the stereochemistry of psorospermin in topoisomerase II–induced alkylation of DNA and in vitro and in vivo biological activity
| Autor: | Michael K. Schwaebe, Laurence H. Hurley, Thomas S. Dexheimer, Mary Gleason-Guzman, Ingrid M. Fellows, Jeffrey P. Whitten, Hariprasad Vankayalapati |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Cancer Research Time Factors Lymphoma Molecular model Stereochemistry Xanthones Mice Nude In Vitro Techniques Alkylation Deoxycytidine Cell Line Inhibitory Concentration 50 Mice chemistry.chemical_compound In vivo Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Animals Leukemia biology Chemistry Topoisomerase Body Weight Stereoisomerism Biological activity DNA Gemcitabine In vitro Pancreatic Neoplasms DNA Topoisomerases Type II Models Chemical Oncology biology.protein Epoxy Compounds Drug Screening Assays Antitumor Enantiomer |
| Zdroj: | Molecular Cancer Therapeutics. 4:1729-1739 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-05-0183 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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