Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity.
5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.
Singh
Sudhir K
SK
Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020, USA.
Ruchelman
Alexander L
AL
Li
Tsai-Kun
TK
Liu
Angela
A
Liu
Leroy F
LF
LaVoie
Edmond J
EJ
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000588:Amines; D000970:Antineoplastic Agents; D009287:Naphthyridines; D009574:Nitro Compounds; D004264:DNA Topoisomerases, Type I