Yunlong Song1, Zhiyu Shao, Thomas S Dexheimer, Evan S Scher, Yves Pommier, Mark Cushman. 1. 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.
Abstract
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.
On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and n class="Chemical">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 humanleukemia, ovarian, and breast cancer cells.
Authors: M Cushman; M Jayaraman; J A Vroman; A K Fukunaga; B M Fox; G Kohlhagen; D Strumberg; Y Pommier Journal: J Med Chem Date: 2000-10-05 Impact factor: 7.446
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Authors: Andrew Morrell; Michael Placzek; Seth Parmley; Smitha Antony; Thomas S Dexheimer; Yves Pommier; Mark Cushman Journal: J Med Chem Date: 2007-08-15 Impact factor: 7.446