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The synthesis of 10-alkyl analogues of the potent antitumor agent 8,10-dideazaminopterin is described. Alkylation of appropriate alpha-alkyl homoterephthalate esters with 2,4-diamino-6-(bromomethyl)-8-deazapteridine afforded 10-alkyl-10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid diesters. Ester cleavage and decarboxylation at C-10 were accomplished by heating with sodium cyanide in Me2SO at 170-180 degrees C to afford the 2,4-diamino-10-alkyl-8,10-dideazapteroic acids. The acids were coupled with diethyl glutamate, followed by saponification, to give the 10-alkyl-8,10-dideazaminopterins. The compounds were potent inhibitors of growth in folate-dependent bacteria, Streptococcus faecium and Lactobacillus casei. The 10-methyl and 10-ethyl analogues gave the highest percent increases in life span for mice infected with L1210 leukemia with ILS values of +203 and +235%, respectively.

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Gabaculine (6, R = H), a naturally occurring amino acid,2 is a potent inhibitor of 4-aminobutyrate:2-oxoglutarate animotransferase (GABA-T), the major GABA catabolizing enzyme. Blocking of this enzyme leads to a buildup of GABA brain levels which may be useful in the treatment of certain diseases characterised by a deficiency of GABA function, e.g., Parkinsonism,3 epilepsy and, Schizophrenia.4 The synthesis of analogues for pharmacological examination is therefore desirable. The enzyme-activated mechanism of action of gabaculine has been studied5 and is shown in Scheme I.