The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo23-dpyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents1a-e

摘要

Novel classical antifolates (>3 and >4) and 17 nonclassical antifolates (>11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of >3, >4, and >11->27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, >31 and >38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I2. The condensation of α-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues >3 and >4, the ester precursors were deprotected, coupled with diethyl-l-glutamate, and saponified. Compounds >3 (IC50 = 60 nM) and >4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound >3 inhibited tumor cells in culture with GI50 ≤ 10⁻⁷ M. Nonclassical >17 (IC50 = 58 nM) was a potent inhibitor of Toxoplasma gondii (T. gondii) DHFR with >500-fold selectivity over human DHFR. Analogue >17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.