title: Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Michael S
authors.initials: MS
authors.lastname: Placzek
authors.forename: Jamin D
authors.initials: JD
authors.lastname: Steffen
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D007769:Lactams; D011725:Pyridines; D059004:Topoisomerase I Inhibitors