Synthesis, Cell Growth Inhibition, and Antitumor Screening of 2-(p-n-Butylanilino)purines and Their Nucleoside Analogues

Article abstract of DOI:10.1021/jm00384a019

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-<(2-hydroxyethoxy)methyl>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 <3H>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-<(2-hydroxyethoxy)methyl> group were nearly as potent inhibitors of <3H>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).