Synthesis and evaluation of indenoisoquinoline topoisomerase I inhibitors substituted with nitrogen heterocycles.
In connection with an ongoing investigation of indenoisoquinoline topoisomerase I (Top1) inhibitors as potential therapeutic agents, the pharmacophore possessing di(methoxy) and methylenedioxy substituents was held constant, and new derivatives were synthesized with nitrogen heterocycles appended to the lactam side chain. Compounds were evaluated for Top1 inhibition and for cytotoxicity in the National Cancer Institute's human cancer cell screen. Some of the more potent derivatives were also screened for in vivo activity in a hollow fiber assay. The results of these studies indicate that lactam substituents possessing nitrogen heterocycles can provide highly cytotoxic compounds with potent Top1 inhibition. Molecular modeling of these compounds in complex with DNA and Top1 suggests that some of the lactam substituents are capable of interacting with the DNA base pairs above and below the site of intercalation and/or with Top1 amino acid residues, resulting in increased biological activity.
Nagarajan
Muthukaman
M
Department of Medicinal Chemistry and Molecular Pharmacology, and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Morrell
Andrew
A
Ioanoviciu
Alexandra
A
Antony
Smitha
S
Kohlhagen
Glenda
G
Agama
Keli
K
Hollingshead
Melinda
M
Pommier
Yves
Y
Cushman
Mark
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry
D000970:Antineoplastic Agents; D007093:Imidazoles; D007192:Indenes; D007546:Isoquinolines; D007769:Lactams; D009025:Morpholines; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D059004:Topoisomerase I Inhibitors; D014230:Triazoles; D004264:DNA Topoisomerases, Type I