Investigation of the Lactam Side Chain Length Necessary for Optimal Indenoisoquinoline Topoisomerase I Inhibition and Cytotoxicity in Human Cancer Cell Cultures

• Published in: Journal of medicinal chemistry 2007-05, Vol.50 (9), p.2040-2048
• Main Authors: Morrell, Andrew, Placzek, Michael S, Steffen, Jamin D, Antony, Smitha, Agama, Keli, Pommier, Yves, Cushman, Mark
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Drug Screening Assays, Antitumor; General aspects; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Pyridines - chemistry; Topoisomerase I Inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0613119

Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0−12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2−4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.