Purines, pyrimidines, and imidazoles. Part 50. Inhibition of adenylosuccinate AMP-lyase no. 4.3.2.2. by derivatives of N-(5-amino-1-β-D-ribofuranosylimidazole-4-carbonyl)-L-aspartic acid 5′-phosphate (SAICAR) and virazole 5′-phosphate

Abstract

N-(5-Amino-1-β-D-ribofuranosyl-4-carbonyl)-L-aspartic acid 5′-phosphate (SAICAR) and some related imidazole peptides have been shown to form in low yield in aqueous solution from the appropriate imidazolecarboxylic acid, an amino-acid or ester and the soluble carbodi-imide 1-cyclohexyl-3-(4-ethylmorpholin-2-yl)carbodi-imide methotoluene-4-sulphonate. Benzyl aminocyanoacetate either with N-(2,3-O-isopropylidene-β-D-ribofuranosyl)-N′dimethylformamidine, or with triethyl orthoformate followed by 2,3-O-isopropylidene-D-ribofuranosylamine, produced a readily separated mixture of benzyl 5-amino-1 -(2,3-O-isopropylidene-α- and -β-D-ribofuranosyl)imidazole4-carboxylates. Phosphorylation of the β-anomer and acid hydrolysis and hydrogenation of the product gave 5-amino-1 -β-D-ribofuranosylimidazole-4-carboxylic acid 5′-phosphate, which was active as a substrate for the enzyme phosphoribosylaminoimidazole succinocarboxamide. The β-benzyl ester with acetic anhydride gave the 5′-O-acetate, with acetyl chloride the 5-N,5′-O-diacetate, and with dimethylformamide dimethyl acetal the 5-N-dimethylaminomethylene derivative. Hydrogenation of the β-anomer or its 5′-O-acetyl derivative and condensation of the resulting carboxylic acids with acetic anhydride gave 3-methyl-5-(2,3-O-isopropylidene-5-O-acetyl-β-D-ribofuranosyl)imidazo[4,5-d][1,3]oxazin-1-one. The 5′-O-acetyl ester was hydrogenated and the carboxylic acid condensed in situ with N-hydroxysuccinimide and dicyclohexylcarbodi-imide to produce N-succinimidyl 5-amino-l-(2,3-O-isopropylidene-5-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate which with dimethyl L-aspartate or diethyl threo-DL-β-methylaspartate produced the corresponding peptides, which were deacylated and phosphorylated to give, after removal of the isopropylidene groups, SAICAR and threo-DL-β-methyl-SAICAR respectively. The threo-derivative and virazole-5′-phosphate both inhibit adenylosuccinase and their effects on this enzyme and on SAICAR-kinosynthetase and AIR-carboxylase are compared.