2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7trifluoromethylquinoxalines as anticancer agents Inhibitors of folate enzymes

Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 Human tumors cell lines a tNational Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme,with a Ki of 0.2 mM .Docking studies were performer on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assale versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inibite hDHFR with Ki values included between 0.2 and 11 mM, while only a few (6,21,24,27,29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performer by NCI, first against the three cell line panel, and only the most active compounds (17,21,24,26,27) wereevaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI 50 equal to 5.49 and log LC 50 equal to 4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 mM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration esamine (100-0.01 microM).