2'-O-Acyl-6-thioinosine cyclic 3',5'-phosphates as prodrugs of thioinosinic acid

Abstract

A series of 2''-O-acyl derivatives of 6-thioinosine cyclic 3'',5''-phosphate (6-HS-cRMP) were prepared and examined for their cytotoxic effects on S49 mouse lymphoma cells which were deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). Cytotoxicity increased with the lipophilicity of the acyl group to a lowest EC50 [median effective concentration] of 65 .mu.M for the 2''-O-palmityl derivative. Addition of a mutation in the gene for cAMP-dependent protein kinase to the HGPRTase-deficient cell line confers resistance to 2''-O-butyryl-cAMP but not to 2''-O-butyryl-6-HS-cRMP; the latter does not exert its toxic effect via activation of protein kinase. The time course of cell kill by 2''-O-palmityl-6-HS-cRMP resembled that of 6-mercaptopurine and not that of cAMP in these cells. Apparently the intact cyclic nucleotides penetrate the cells and are converted by phosphodiesterase action and deacylation to the 1st toxic metabolite of 6-mercaptopurine, thioinosinic acid.