Synthesis of new dihydroindeno[1,2-c]isoquinoline and indenoisoquinolinium chloride topoisomerase I inhibitors having high in vivo anticancer activity in the hollow fiber animal model.
A number of novel dihydroindenoisoquinolines and indenoisoquinolinium salts were synthesized and examined for cytotoxicity in cancer cell cultures and for inhibition of topoisomerase I (top1). The top1-mediated DNA cleavage patterns produced in the presence of several of the new analogues were also investigated, and a few of the more potent compounds were examined for activity in hollow fiber animal models. Very cytotoxic dihydroindenoisoquinoline and isoquinolinium salts were obtained with mean graph midpoints (MGMs) for growth inhibition in the low submicromolar range. Two of the new dihydroindenoisoquinolines were found to be weaker top1 inhibitors than the lead compound 1, while two of the indenoisoquinolinium salts were more potent. The top1-mediated DNA cleavage patterns of the indenoisoquinolines examined were found to be similar to each other but different from that of camptothecin. Several of the more potent indenoisoquinolines displayed promising anticancer activities in hollow fiber animal models.
Jayaraman
Muthusamy
M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Fox
Brian M
BM
Hollingshead
Melinda
M
Kohlhagen
Glenda
G
Pommier
Yves
Y
Cushman
Mark
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors