Effects of the chiral isomers of erythro- and threo-9-(2-hydroxy-3-nonyl)adenine on purine metabolism in sarcoma 180 cells.

The effects of the chiral isomers of erythro- and threo-9-(2-hydroxy-3-nonyl)adenines (EHNA and THNA) on purine metabolism in Sarcoma 180 cells have been determined. At concentrations of 10-80 microM [10- to 1000-fold greater than their Ki values with adenosine deaminase (ADA)], all isomers inhibited purine salvage and biosynthesis de novo. Although (+)-EHNA, the most potent ADA inhibitor, exerted the greatest effects, there was no direct correlation between the potency of ADA inhibition and the secondary effects on purine metabolism, e.g. (+)-EHNA is about 2-fold more inhibitory than (-)-EHNA in blocking purine base incorporation but about 250-fold more potent as an inhibitor of ADA (Ki of (+)-EHNA = 2 nM; Ki of (-)-EHNA = 500 nM [Bessodes et al., Biochem. Pharmac. 31, 879 (1982)]). All the isomers inhibited the incorporation of radiolabeled purine bases (adenine, guanine and hypoxanthine) and nucleosides (guanosine and inosine) into acid-soluble nucleotides and of glycine into 5'-phosphoribosyl-formylglycineamide. Unlike the results of Henderson et al. [Biochem. Pharmac. 26, 1967 (1977)] with Ehrlich ascites cells, the incorporation of adenosine into nucleotides was only slightly inhibited in Sarcoma 180 cells. (+)-EHNA did not inhibit the activities of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase, purine phosphoribosyltransferases or nucleotide kinases in cell extracts. Accumulation of PRPP was inhibited only under conditions that fostered rapid synthesis.