Esters and amides of 2,3-dimethoxy-8,9-methylenedioxy-benzo[i]phenanthridine-12-carboxylic acid: potent cytotoxic and topoisomerase I-targeting agents.
The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells.
Zhu
Shejin
S
Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Ruchelman
Alexander L
AL
Zhou
Nai
N
Liu
Angela A
AA
Liu
Leroy F
LF
LaVoie
Edmond J
EJ
D000577:Amides / Q000737:chemistry*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D004952:Esters / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D015394:Molecular Structure; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000737:chemistry
D000577:Amides; D004791:Enzyme Inhibitors; D004952:Esters; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin