title: Optimization of the lactam side chain of 7-azaindenoisoquinoline topoisomerase I inhibitors and mechanism of action studies in cancer cells.
abstract: Optimization of the lactam ω-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14-17 and 19 exhibited mean graph midpoint cytotoxicity (GI50) values of 21-71 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline-DNA-Top1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone γ-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA-Top1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development.
authors: 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: Evgeny
authors: E
authors: Kiselev
authors: Dhriti
authors: D
authors: Sooryakumar
authors: Keli
authors: K
authors: Agama
authors: Mark
authors: M
authors: Cushman
authors: Yves
authors: Y
authors: Pommier
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007769:Lactams; D011804:Quinolines; D059004:Topoisomerase I Inhibitors