Nucleoside carbonyl(di- and triphosphates)

Abstract

The first examples of nucleoside di- and triphosphates containing the electrophilic and potentially reactive carbonyl group in place of a phosphoanhydride oxygen are reported, using the DNA polymerase inhibitors N²-(4-butylphenyl)-2′-deoxyguanosine 5′-triphosphate (BuPdGTP) and N²-(4-butylphenyl)-2′-deoxyguanosine 5′-diphosphate (BuPdGDP) as platforms. The P²,P³-carbonyltriphosphonate, BuPdGMPPCOP, was obtained by reaction between the phosphoro-N-methylimidazolidate of the monophosphate BuPdGMP and carbonyldiphosphonic acid (PCOP), and it was isolated by preparative reverse phase chromatography. The carbonyldiphosphonate analogue, BuPdGMPCOP, was obtained by displacement of the 5′-mesyl group of the corresponding 5′-mesylnucleoside with carbonyldiphosphonate. While BuPdGMPCOP was stable in aqueous solutions, BuPdGMPPCOP hydrolyzed to BuPdGMP and PCOP with a half-life of 3 hours. Both BuPdGMPPCOP and BuPdGMPCOP were potent, competitive inhibitors of human DNA polymerase α.