Quinazoline Antifolate Thymidylate Synthase Inhibitors: γ-Linked l-d, d-d, and d-l Dipeptide Analogues of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic Acid (ICI 198583),

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Abstract
The syntheses of γ-linked l-d, d-d, and d-l dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) are described. The general methodology for the synthesis of these molecules involved the preparation of the dipeptide derivatives employing solution phase peptide synthesis followed by condensation of the dipeptide free bases with the appropriate pteroic acid analogue via diethyl cyanophosphoridate (DEPC) activation. In the final step, tert-butyl esters were removed by trifluoroacetic acid (TFA) hydrolysis. Z-l-Glu-OBut-γ-d-Ala-OBut, for example, was prepared from α-tert-butyl N-(benzyloxycarbonyl)-l-glutamate and tert-butyl d-alaninate via isobutyl-mixed anhydride coupling. The Z-group was removed by catalytic hydrogenolysis and the resulting dipeptide free base condensed with 2-desamino-2-methyl-N10-propargyl-5,8-dideazapteroic acid via DEPC coupling. Finally, tert-butyl esters were removed by TFA hydrolysis to give ICI 198583-γ-d-Ala. The compounds were tested as inhibitors of thymidylate synthase and L1210 cell growth. Good enzyme and growth inhibitory activity were found with γ-linked l-d dipeptides, the best examples being the Glu-γ-d-Glu derivative 35 (Ki = 0.19 nM, L1210 IC50 = 0.20 ± 0.017 μM) and the Glu-γ-d-α-aminoadipate derivative 39 (Ki = 0.12 nM, L1210 IC50 = 0.13 ± 0.063 μM). In addition, ICI 198583 l-γ-d-linked dipeptides were resistant to enzymatic degradation in mice.