title: Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors.
abstract: The indenoisoquinolines represent a class of non-camptothecin topoisomerase I (Top1) inhibitors that exert cytotoxicity by trapping the covalent complex formed between DNA and Top1 during relaxation of DNA supercoils. As an ongoing evaluation of Top1 inhibition and anticancer activity, indenoisoquinolines were linked via their lactam side chains to provide polyamines end-capped with intercalating motifs. The resulting bisindenoisoquinolines were evaluated for cytotoxicity in the National Cancer Institute's human cancer cell screen and for Top1 inhibition. Preliminary findings suggested that the 2-3-2 and 3-3-3 linkers, referring to the number of carbons between nitrogen atoms, were optimal for both potent Top1 inhibition and cytotoxicity. Using optimized linkers, bisindenoisoquinolines were synthesized with nitro and methoxy substituents on the aromatic rings. The biological results for substituted compounds revealed a disagreement between the structure-activity relationships of monomeric indenoisoquinolines and bisindenoisoquinolines as Top1 inhibitors, but cytotoxicity was maintained for both series of compounds.
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: Muthukaman
authors.initials: M
authors.lastname: Nagarajan
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Glenda
authors.initials: G
authors.lastname: Kohlhagen
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ragazzon
authors.forename: Nichola C
authors.initials: NC
authors.lastname: Garbett
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Chaires
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; 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*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007192:Indenes; D007546:Isoquinolines; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; D004247:DNA