Quinazoline antifolates inhibiting thymidylate synthase: computer modelling of the N10 substituent.

The synthesis and biological properties of N10-(2,2,2-trifluoroethyl)-5, 8-dideazafolic acid are described. It was fivefold less active as an inhibitor of L1210 thymidylate synthase (TS) than its N10-ethyl congener and sevenfold less active as an inhibitor of the growth of L1210 cells in culture. CNDO calculations were performed on the following N10 substituents in a model fragment of 5, 8-dideazafolic acid: propargyl, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl and methyl. The resulting values of partial charge on the distal terminus of the substituent correlated with the TS inhibition induced by the substituent. In particular, the mildly net positive charge on the acetylenic hydrogen in the propargyl substituent (+0.064) was not matched by any other in the series. N10-propargyl-5, 8-dideazafolic acid continues as the best inhibitor in this series.