Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors.
The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622. Despite an imperfect correlation between cytotoxicities and topoisomerase I inhibition results, the hypothetical structural model of the cleavage complex presented here provides a conceptual framework to explain the structure-activity relationships.
Xiao
Xiangshu
X
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Antony
Smitha
S
Kohlhagen
Glenda
G
Pommier
Yves
Y
Cushman
Mark
M
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004247:DNA