Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings.
The indenoisoquinolines are a class of cytotoxic topoisomerase I inhibitors that offer certain advantages over the camptothecins, including the greater stabilities of the compounds themselves, as well as the greater stabilities of their drug-enzyme-DNA cleavage complexes. To investigate the possible biological roles of the di(methoxy) and methylenedioxy substituents present on the aromatic rings of the previously synthesized indenoisoquinoline topoisomerase I inhibitors, a series of compounds lacking these substituents was synthesized and tested for both cytotoxicity in cancer cell cultures and for enzyme inhibitory activity. The results indicate that the aromatic substituents make a small, but consistently observable contribution to the biological activity. Molecular models derived for the binding of the unsubstituted indenoisoquinolines in ternary complex with DNA and topoisomerase I indicate that the substituents on the lactam nitrogen project out of the major groove, and the carbonyl group is directed out of the minor groove, where it is involved in a hydrogen bonding interaction with the side chain guanidine group of Arg364. The DNA cleavage patterns observed in the presence of topoisomerase I and various indenoisoquinolines were similar, although significant differences were detected. There were also variations in the DNA cleavage pattern seen with camptothecin vs the indenoisoquinolines, which indicates that these two classes of topoisomerase I inhibitors are likely to target the cancer cell genome differently, resulting in different spectra of anticancer activity. The most cytotoxic of the presently synthesized indenoisoquinolines has a 4-amino-n-butyl group on the lactam nitrogen.
Nagarajan
Muthukaman
M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Morrell
Andrew
A
Fort
Brian C
BC
Meckley
Marintha Rae
MR
Antony
Smitha
S
Kohlhagen
Glenda
G
Pommier
Yves
Y
Cushman
Mark
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I