Synthesis and Characterization of N2-(p-n-Butylphenyl)-2'-deoxyguanosine and Its 5'-Triphosphate and Their Inhibition of HeLa DNA Polymerase α

Article abstract of DOI:10.1021/jm00368a012

N²-(p-n-Butylphenyl)-2'-deoxyguanosine (BuPdG) and its 5'-triphosphate (BuPdGTP), expected to be inhibitors of eukaryotic DNA polymerase α, have been synthesized.BuPdG was synthesized by two methods and characterized by 1H NMR and by chemical relation to guanosine.Direct synthesis involving silylated N²-(p-n-butylphenyl)guanine (BuPG) and 1-chloro-3,5-di-p-toluoyl-2-deoxyribofuranose in the presence of trimethylsilyl trifluoromethanesulfonate gave one α and two β isomers of deoxyribonucleoside as determined by 1H NMR.However, NMR and UV spectra were equivocal in distinguishing between 7 and 9 isomers.The identity of the desired 9-β-BuPdG was ultimately proved by its independent synthesis from the corresponding ribonucleoside. 1H NMR spectra of the O'-acetylated ribonucleosides of BuPG showed characteristic patterns of O'-acetylated quanosines, and their identity was proved by relating the products of the reaction of isomeric O'-acetyleted 2-bromoinosines with p-n-butylaniline and with ammonia: the 2-bromoinosine which gave guanosine also gave the suspected 9-β-ribonucleoside, BuPGr, and that which gave N⁷-β-ribofuranosylguanine also gave the 7-β isomer of BuPGr.BuPGr was transformed in a multistep procedure to give BuPdG, identical with the major β isomer obtained by direct deoxynucleoside synthesis.The 5'-monophosphate of BuPdG was obtained by treatment of the nucleoside with phosphoryl chloride in trimethyl phosphate; the monophosphate reacted as the phosphoimidazolyl derivative with pyrophosphate to yield the 5'-triphosphate, BuPdGTP.The BuPG deoxynucleosides inhibited DNA polymerase α from HeLa cells with potencies similar to that found for BuPG itself.BuPdGTP, however, was at least a 1000-fold more potent inhibitor of DNA polymerase α than BuPG.