Synthesis of (dialkylamino)alkyl-disubstituted pyrimido[5,6,1- de]acridines, a novel group of anticancer agents active on a multidrug resistant cell line.
A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
Antonini
I
I
Department of Chemical Sciences, University of Camerino, Italy.
Cola
D
D
Polucci
P
P
Bontemps-Gracz
M
M
Borowski
E
E
Martelli
S
S
D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D014407:Tumor Cells, Cultured
D000166:Acridines; D000970:Antineoplastic Agents