Bioactivity of synthetic 2-halo-3-aryl-4(3H)-quinazoliniminium halides in L1210 leukemia and SK-BR-3 mammary tumor cells in vitro.

ABSTRACT

BACKGROUND: Because quinazolines and their derivatives exhibit a wide range of pharmacological profiles, there is a continuous interest among synthetic and medicinal chemists in the discovery of more potent analogs. Ten novel quinazoliniminium salts were synthesized and tested for their effectiveness against murine and human tumor cell proliferation in vitro. MATERIALS AND METHODS: Various markers of tumor cell metabolism, DNA degradation and mitotic disruption were assayed in vitro to evaluate drug cytotoxicity. RESULTS: All compounds induced concentration- and time-dependent antitumor effects in vitro but the 2-chloro-3-(4-methoxyphenyl)quinazolin-4(3H)-iminium chloride (4) was the most effective inhibitor of leukemia L1210 cell proliferation at days 2-4 (IC50 2.1-0.9 µM), suggesting that the para-methoxyphenyl substituent on the N3 of 4 may enhance the antiproliferative properties of the quinazoliniminium scaffold. In mammary SK-BR-3 tumor cells, 4 reduced the Ki-67 marker of cell proliferation at 24 h and the metabolic activity at days 2 and 4. Moreover, a 1.5- or 3-h treatment with 4 was sufficient to inhibit the rates of DNA, RNA and protein syntheses measured in L1210 cells over 0.5- or 1-h periods of pulse-labeling with 3H-thymidine, 3H-uridine and 3H-leucine, respectively. As 4 did not reduce the fluorescence of the ethidium bromide-DNA complex, this compound was unlikely to directly bind to or destabilize double-stranded DNA. However, 4 induced DNA cleavage at 24 h in L1210 cells containing 3H-thymidine-prelabeled DNA, suggesting that this antitumor drug might trigger an apoptotic pathway of DNA fragmentation. After 12-48 h, 4 weakly increased the mitotic index of L1210 cells but stimulated the formation of many binucleated cells, multinucleated cells and micronuclei, suggesting that this antitumor compound might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis. CONCLUSION: Although 4 may have interesting bioactivity, more compounds based on the quinazoliniminium scaffold must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action.