Pyrimido [4,5,6-kl] acridines, a new class of potential anticancer agents. Synthesis and biological evaluation.
A series of 3-(aminoalkyl)-2,7-dihydro-6-nitropyrimido [4,5,6-kl] acridin-2-ones 3, strictly related to the pyrazoloacridines 1, have been synthesized. Thus, the reaction of the suitable 1-(aminoalkyl)amino-9, 10-dihydro-9-imino-4-nitroacridine 2 with ethyl chloroformate afforded the pyrimidoacridines 3a-f. By hydrolysis in hydrobromic acid of the 10-methoxy derivatives 3d-f, the 10-hydroxy derivatives 3g-i were obtained. The pyrimidoacridines 3a-i were tested in vitro for their cytotoxic activity against L1210 murine leukemia and HT29 human colon adenocarcinoma cell lines, showing significant potency of growth inhibition. Different DNA-binding assays as well as attempts to correlate cytotoxicity and DNA affinity have been carried out.
Antonini
I
I
Department of Chemical Sciences, University of Camerino, Italy.
Polucci
P
P
Cola
D
D
Bontemps-Gracz
M
M
Pescalli
N
N
Menta
E
E
Martelli
S
S
D000166:Acridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D014407:Tumor Cells, Cultured
D000166:Acridines; D000970:Antineoplastic Agents; D004247:DNA