Carboxylic acid bioisosteres of γ-linked dipeptide analogues of the folate-based thymidylate synthase (TS) inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Tetrazole carboxylic acid bioisosteres of γ-linked dipeptide derivatives of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583), a folate-based inhibitor of thymidylate synthase (TS), were synthesised by multistep routes starting from the appropriate pteroic acid analogue and Z- -Ala or -Glu. They exhibited excellent TS inhibitory activities which, however, were not accompanied by a parallel improvement in the L1210 cell growth inhibition.