Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity.
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.
Fellows
Ingrid M
IM
The University of Texas at Austin, USA.
Schwaebe
Michael
M
Dexheimer
Thomas S
TS
Vankayalapati
Hariprasad
H
Gleason-Guzman
Mary
M
Whitten
Jeffrey P
JP
Hurley
Laurence H
LH
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001835:Body Weight; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D013237:Stereoisomerism; D013997:Time Factors; D044004:Xanthones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry*; D000093542:Gemcitabine
D004852:Epoxy Compounds; D044004:Xanthones; D003841:Deoxycytidine; C025543:psorospermin; D004247:DNA; D004250:DNA Topoisomerases, Type II; D000093542:Gemcitabine