FOLATE-BASED INHIBITORS OF THYMIDYLATE SYNTHASE - SYNTHESIS AND ANTITUMOR-ACTIVITY OF GAMMA-LINKED STERICALLY HINDERED DIPEPTIDE ANALOGS OF-DESAMINO-2-METHYL-N-10-PROPARGYL-5,8-DIDEAZAFOLIC ACID (ICI-198583)

In an effort to synthesize inhibitors of thymidylate synthase (TS) tha t do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 , 8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or pro pargyl group was incorporated into the gamma-glutamyl amide bond of ga mma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583 -gamma-L-Glu. In addition, steric bulk was introduced on either side o f the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamm a-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeG lu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydroly sis but poorer inhibitors of TS and L1210 cell growth. However, introd uction of 7-Me, 2'-F substitution into the quinazoline nucleus gave si gnificant improvement in the inhibitory activity against thymidylate s ynthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gam ma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respecti vely, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios f or the L1210:R-D1694/L1210 cell line indicated that 28-30 do not under go polyglutamation.