Nitrated indenoisoquinolines as topoisomerase I inhibitors: a systematic study and optimization.
The biological activity of indenoisoquinoline topoisomerase I (Top1) inhibitors can be greatly enhanced depending on the choice of substituents on the aromatic rings and lactam side chain. Previously, it was discovered that a 3-nitro group and a 9-methoxy group afforded enhanced biological activity. In the present investigation, indenoisoquinoline analogues were systematically prepared using combinations of nitro groups, methoxy groups, and hydrogen atoms in an effort to understand the contribution of each group toward cytotoxicity and Top1 inhibition. Analysis of the biological results suggests that the nitro group is important for Top1 inhibition and the methoxy group improves cytotoxicity. In addition, previously identified structure-activity relationships were utilized to select favorable lactam side chain functionalities for incorporation on the aromatic skeleton of analogues in this study. As a result, this investigation has provided optimal Top1 inhibitors equipotent to camptothecin that demonstrate low nanomolar cytotoxicities toward cancer cells.
Morrell
Andrew
A
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Placzek
Michael
M
Parmley
Seth
S
Antony
Smitha
S
Dexheimer
Thomas S
TS
Pommier
Yves
Y
Cushman
Mark
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; 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; D008958:Models, Molecular; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D009574:Nitro Compounds; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I