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).