Syntheses of .alpha.- and .gamma.-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism

摘要: N-[4-[[(Benzyloxy)carbonyl]methylamino]benzoyl]-L-glutamic acid alpha-benzyl ester (2) and gamma-benzyl (6) served as key intermediates in syntheses of precursors to amides peptides methotrexate (MTX) involving both the alpha- gamma-carboxyl groupings glutamate moiety. Coupling 2 6 at open carboxyl grouping with amino compounds was affected by mixed anhydride method (using isobutyl chloroformate); acids coupled were protected benzyl esters. gamma-methyl (5), a precursor MTX ester, prepared from L-glutamic 4-[[(benzyloxy)carbonyl]methylamino]benzoyl chloride (1) manner similar that used prepare 6. The alpha-methyl treatment MeI DMF containing (i-Pr)2NEt. Benzyl (benzyloxy)carbonyl protective removed hydrogenolysis, deprotected side-chain converted gamma-substituted amides, peptides, esters alkylation 6-(bromomethyl)-2,4-pteridinediamine hydrobromide (12). Biochemical-pharmacological studies on aided establishing alpha-carboxyl moiety contributes binding dihydrofolate reductase while does not. Other peptide MTX-gamma-Glu (13h) are concerned contribution toward antifolate activity this metabolite MTX. also evaluated compared respect cytotoxicity H.Ep.-2 cells effect L1210 murine leukemia.