2'-O-Acyl-6-thioinosine cyclic 3',5'-phosphates as prodrugs of thioinosinic acid.
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 of 65 micrometer 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, indicating that 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 cyclic AMP in these cells. The data suggest that the intact cyclic nucleotides are penetrating the cells and being converted, by phosphodiesterase action and deacylation, to the first toxic metabolite of 6-mercaptopurine, thioinosinic acid.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000242:Cyclic AMP / Q000494:pharmacology; D004351:Drug Resistance; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007288:Inosine / Q000031:analogs & derivatives*; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009712:Nucleotides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013873:Thionucleotides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
D000970:Antineoplastic Agents; D009712:Nucleotides, Cyclic; D013873:Thionucleotides; D013868:Thioinosine; D007288:Inosine; D000242:Cyclic AMP; D007041:Hypoxanthine Phosphoribosyltransferase