| Abstract
| - In an effort to synthesize inhibitors of thymidylate synthase (TS)that do not undergopolyglutamation, a series of γ-linked sterically hindered dipeptideanalogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI198583) was prepared. A methyl, ethyl, orpropargyl group was incorporated into the γ-glutamyl amide bond ofγ-linked l,l dipeptidederivatives of ICI 198583, such as ICI 198583-γ-l-Glu.In addition, steric bulk was introducedon either side of the γ-glutamyl bond of ICI198583-γ-l-Glu or ICI 198583-γ-l-Ala.The resultingdipeptide analogues, e.g., ICI 198583-γ-MeGlu and ICI198583-γ-Aib, were apparently stableto in vivo hydrolysis but poorer inhibitors of TS and L1210cell growth. However, introductionof 7-Me, 2‘-F substitution into the quinazoline nucleus gavesignificant improvement in theinhibitory activity against thymidylate synthase. Compounds28−30, the 7-Me, 2‘-F derivativesof ICI 198583-γ-MeGlu, ICI 198583-γ-EtGlu, and ICI198583-γ-PgGlu, respectively, were potentinhibitors of TS (Kiapp = 0.21−1.1 nM) andL1210 cell growth (IC50 = 0.05−0.34 μM) andweresimilar to that seen with the most potent γ-linkedl,d dipeptide derivatives of ICI198583previously synthesized. Furthermore, the low cross-resistanceratios for the L1210:RD1694/L1210cell line indicated that 28−30 do not undergopolyglutamation.
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