SYNTHESIS AND ANTITUMOR-ACTIVITY OF 10-PROPARGYL-10-DEAZAAMINOPTERIN

Successive alkylation of dimethyl homoterephthalate with propargyl bro mide and 2,4-diamino-6-(bromomethyl)pteridine followed by ester saponi fication at room temperature afforded no-4-deoxy-10-carboxy-10-proparg yl-10-deazapteroic acid. The 10-COOH was readily decarboxylated by hea ting in DMSO at a temperature of only 120-degrees-C to yield the diami no-10-propargyl-10-deazapteroic acid intermediate. Coupling with dieth yl L-glutamate and ester hydrolysis gave the title compound. The 10-pr opargyl analogue was about 5 times more potent than MTX as an inhibito r of growth in L1210 cells, but was only one-third as potent as an inh ibitor of DHFR from L1210. The analogue was transported inward very ef fectively in L1210 cells showing a 10-fold advantage over MTX. At a do se of 36 mg/kg the 10-propargyl compound caused shrinkage of the E0771 solid murine mammary tumor to only 1 % of untreated controls.