Methotrexate analogues. 9. Synthesis and biological properties of some 8-alkyl-7,8-dihydro analogues.

A series of 8-alkyl-7,8,-dihydromethotrexate analogues was prepared by direct alkylation of 7,8-dihydromethotrexate, after pilot studies were performed with simpler pteridines. These compounds are tested for in vitro inhibitory activity against Lactobacillus casei and as enzyme inhibitors against dihydrofolate reductase and thymidylate synthetase derived from this organism. All of the analogues were less inhibitory toward dihydrofolate reductase than was methotrexate but were more inhibitory toward thymidylate synthetase. The analogues were also evaluated for in vitro inhibitory activity against the CCRF-CEM human lymphoblastic leukemia cells. In vivo against the L-1210 leukemia in mice, several of the analogues exhibited some antileukemic activity.