Inhibition of purine biosynthesis de novo in sarcoma 180 ascites cells by mercapto and seleno purine analogs

Abstract

6-Methylmercaptopurine ribonucleoside (MeMPR) is the most potent inhibitor known of PRPP amidotransferase, the first step in purine biosynthesis de novo. We have examined other 6-methylmercapto- and 6-methylselenopurine ribonucleosides for their ability to act as feedback inhibitors of this pathway as well as for their ability to form analog nucleotides. Methylmercaptopurine ribonucleoside (MeMPR), methylselenopurine ribonucleoside (MeSePR), and methylmercaptopyrazolo pyrimidine ribonucleoside (MeMPPR) were potent inhibitors (90 per cent), methylselenopyrazolo pyrimidine ribonucleoside (MeSePPR) was less potent (75 per cent), and methylselenoguanosine (MeSeGR) did not significantly inhibit this pathway. Large amounts of the corresponding 5'-monophosphate nucleosides were formed from MeMPR and MeMPPR, lesser amounts from MeSePPR and MeSePR and none from MeSeGR. The ability of 6-selenoguanine, its ribonucleoside and the α- and β-anomers of the deoxyribonucleoside were also examined as possible inhibitors of purine synthesis de novo. Further investigation is needed to determine if these compounds have significant activity as antineoplastic agents, but in any case they may lead to structural modifications which will produce active compounds.