Folate-Based Inhibitors of Thymidylate Synthase: Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic Acid (ICI 198583)

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Abstract
In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of γ-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the γ-glutamyl amide bond of γ-linked l,l dipeptide derivatives of ICI 198583, such as ICI 198583-γ-l-Glu. In addition, steric bulk was introduced on either side of the γ-glutamyl bond of ICI 198583-γ-l-Glu or ICI 198583-γ-l-Ala. The resulting dipeptide analogues, e.g., ICI 198583-γ-MeGlu and ICI 198583-γ-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2‘-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28−30, the 7-Me, 2‘-F derivatives of ICI 198583-γ-MeGlu, ICI 198583-γ-EtGlu, and ICI 198583-γ-PgGlu, respectively, were potent inhibitors of TS (Kiapp = 0.21−1.1 nM) and L1210 cell growth (IC50 = 0.05−0.34 μM) and were similar to that seen with the most potent γ-linked l,d dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:RD1694/L1210 cell line indicated that 28−30 do not undergo polyglutamation.