87781-94-0Relevant articles and documents
Synthesis, Cell Growth Inhibition, and Antitumor Screening of 2-(p-n-Butylanilino)purines and Their Nucleoside Analogues
Wright, George E.,Dudycz, Lech W.,Kazimierczuk, Zygmunt,Brown, Neal C.,Khan, Naseema N.
, p. 109 - 116 (2007/10/02)
Derivatives of N2-(p-n-butylphenyl)guanine (BuPG) and 2-(p-n-butylanilino)adenine (BuAA) were synthesized and tested as inhibitors of mammalian DNA polymerase α, cell growth, and macromolecule synthesis. 2-(p-n-Butylanilino)-6-chloropurine (BuACl) served as a useful intermediate to prepare a series of 6-substituted analogues.BuACl, as its sodium salt, reacted with 2-deoxy-3,5-di-p-toluoyl-β-D-ribofuranosyl chloride in acetonitrile to give 64percent of the corresponding 9-β nucleoside (blocked BuAdCl) and only 14percent of the 7-β isomer.Deblocking and substitution of chlorine in BuAdCl generated a series of 2-(p-n-butylanilino)-9-(2-deoxy-β-D-ribofuranosyl)purine derivatives.Reaction of the sodium salt of BuACl with (2-acetoxyethoxy)methyl bromide also afforded, after deblocking and substitution of 6-chloro group, a series of 2-(p-n-butylanilino)-9-purines.The bases synthesized were inhibitors of DNA polymerase α isolated from Chinese hamster ovary cells, the most potent compounds being 6-methoxy and 6-methylthio derivatives of 2-(p-n-butylanilino)purine.When tested for their ability to inhibit thymidine incorporation into DNA in HeLa cell cultures and the growth of expotentially growing HeLa cells, 9-(2-deoxy-β-D-ribofuranosyl) derivatives had greater potency than their base counterparts, but "adenine" analogues, such as 2-(p-n-butylanilino)-2'-deoxyadenosine (BuAdA, IC50= 1 μM), were considerably more potent than N2-(p-n-butylphenyl)-2'-deoxyguanosine (BuPdG, IC50= 25 μM).Derivatives bearing the 9- group were nearly as potent inhibitors of thymidine incorporation in these experiments as the corresponding deoxyribonucleotides.Base and deoxynucleoside derivatives also inhibit cellular RNA synthesis, and several compounds, at high concentrations, inhibited protein synthesis.BuPG, BuAA, and four deoxyribonucleoside derivatives of 2-(p-n-butylanilino)purines were tested against P-388 lymphocytic leukemia in mice.None of the compounds increased the survival time of test animals, but two of them, BuAdA and its 6-desamino derivative BuAdP, were lethal at the highest concentration used (400 mg/kg).
Synthesis and Characterization of N2-(p-n-Butylphenyl)-2'-deoxyguanosine and Its 5'-Triphosphate and Their Inhibition of HeLa DNA Polymerase α
Wright, George E.,Dudycz, Lech W.
, p. 175 - 181 (2007/10/02)
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.
