Nucleoside carbonyl(di- and triphosphates)

The rst examples of nucleoside di- and triphosphates containing the electro philic and potentially reactive carbonyl group in place of a phosphoanhydri de oxygen are reported, using the DNA polymerase inhibitors N-2-(4-butylphe nyl)-2'-deoxyguanosine 5'-triphosphate (BuPdGTP) and N-2-(4-butylphenyl)-2' -deoxyguanosine 5'-diphosphate (BuPdGDP) as platforms. The P-2,P-3-carbonyl triphosphonate, BuPdGMPPCOP, was obtained by reaction between the phosphoro -N-methylimidazolidate of the monophosphate BuPdGMP and carbonyldiphosphoni c acid (PCOP), and it was isolated by preparative reverse phase chromatogra phy. The carbonyldiphosphonate analogue, BuPdGMPCOP, was obtained by displa cement of the 5'-mesyl group of the corresponding 5'-mesylnucleoside with c arbonyldiphosphonate. While BuPdGMPCOP was stable in aqueous solutions, BuP dGMPPCOP hydrolyzed to BuPdGMP and PCOP with a half-life of 3 hours. Both B uPdGMPPCOP and BuPdGMPCOP were potent, competitive inhibitors of human DNA polymerase alpha.