Analogs of methotrexate

Analogues of methotrexate (MTX) were prepared by alkylation of side-chain precursors with 6-(bromomethyl)-2,4-pteridinediamine followed, where necessary, by saponification of the intermediate esters and, in two cases, by electrophilic substitution reactions in the pyridine ring portion of 3-deazamethotrexate. Effects of the various modifications on their ability to inhibit dihydrofolate reductase, cytotoxicity, and activity against L1210 leukemia in mice were examined in light of recent findings concerning active transport of MTX and related compounds and the binding features of the MTX-dihydrofolate reductase complex.