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.