title: Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.
abstract: Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3'-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Beck
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Abdelmalak
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Tender
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors