Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors.
On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase I-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenoisoquinoline 5. The desired compound 14a was synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in a series of human leukemia, ovarian, and breast cancer cells.
Song
Yunlong
Y
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
Shao
Zhiyu
Z
Dexheimer
Thomas S
TS
Scher
Evan S
ES
Pommier
Yves
Y
Cushman
Mark
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors