Synthesis and characterization of N2-(p-n-butylphenyl)-2'-deoxyguanosine and its 5'-triphosphate and their inhibition of HeLa DNA polymerase .alpha.

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Abstract
N2-(p-n-Butylphenyl)-2''-deoxyguanosine (BuPdG) and its 5''-triphosphate (BuPdGTP), expected to be inhibitors of eukaryotic DNA polymerase .alpha., have been synthesized. BuPdG was synthesized by 2 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 trifluoromethanesulfoante gave 1 .alpha. and 2 .beta. isomers of deoxyribonculeoside 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-.beta.-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 guanosines, and their identity was proved by relating the products of the reaction of isomeric O''-acetylated 2-bromoinosines with p-n-butylaniline and with ammonia: the 2-bromoinosine which gave guanosine also gave the suspected 9-.beta.-ribonucleoside, BuPGr, and that which gave N7-.beta.-ribofuranosylguanine also gave the 7-.beta. isomer of BuPGr. BuPGr was transformed in a multistep procedure to give BuPdG, identical with the major .beta. 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 .alpha. from HeLa cells with potencies similar to that found for BuPG itself. BuPdGTP, however, was at least a 100-fold more potent inhibitor of DNA polymerase .alpha. than BuPG. [The implications for cancer chemotherapy are discussed.].