Synthesis, cell-growth inhibition, and antitumor screening of 2-(p-n-butylanilino)purines and their nucleoside analogs
- 1 January 1987
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 30 (1), 109-116
- https://doi.org/10.1021/jm00384a019
Abstract
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 .alpha., cell growth, and macromolecule synthesis. 2-(p-n-Butylanilino)-6-chloroquine (BuACl) served as a useful intermediate to prepare a series of 6-substituted analogues. BuACl, as the sodium salt, reacted with 2-deoxy-3,5-di-p-toluoyl-.beta.-D-ribofuranosyl chloride in acetonitrile to give 64% of the corresponding 9-.beta. nucleoside (blocked BuAdCl) and only 14% of the 7-.beta.-isomer. Deblocking and substitution of chlorine in BuAdCl generated a series of 2-(p-n-butylanilino)-9-(2-deoxy-.beta.-D-ribofuranosyl)purine derivatives. Reaction of the sodium salt of BuACl with (2-acetoxyethoxy)methyl bromide also afforded, after deblocking and substitution of the 6-chloro group, a series of 2-(p-n-butylanilino)-9-[(2-hydroxyethoxy)methyl]purines. The bases synthesized were inhibitors of DNA polymerase .alpha. 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 exponentially growing HeLa cells, 9-(2-deoxy-.beta.-D-ribofuranosyl) derivatives had greater potency than their base counterparts, but "adenine" analogues, such as 2-(p-n-butylanilino)-2''-deoxyadenosine (BuAdA, IC50 = 1 .mu.M), were considerably more potent than N2-(p-n-butylphenyl)-2''-deoxyguanosine (BuPdG, IC50 = 25 .mu.M). Derivatives bearing the 9-[(2-hydroxyethoxy)methyl] group were nearly as potent inhibitors of [3H]thymidine incorporation in these experiments as the corresponding deoxyribonucleosides. Base and deoxynucleoside derivatives also inhibited 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).Keywords
This publication has 8 references indexed in Scilit:
- Base-pairing properties of O-methylated bases of nucleic acids energetic and steric considerationsBiophysical Chemistry, 1985
- Purification and characterization of DNA polymerase alpha of chinese hamster ovary cellsMolecular and Cellular Biochemistry, 1985
- Comparative enzymology of ultraviolet-induced DNA repair synthesis and semiconservative DNA replication in permeable diploid human fibroblasts.Journal of Biological Chemistry, 1984
- Synthesis of 2'-deoxytubercidin, 2'-deoxyadenosine, and related 2'-deoxynucleosides via a novel direct stereospecific sodium salt glycosylation procedureJournal of the American Chemical Society, 1984
- Hydroxylamine Mutagenesis: Observation of Inverted Watson‐Crick Base‐Pairing Between N4‐Methoxycytosine and Adenine with the Aid of Natural‐Abundance High‐Resolution 15N NMR SpectroscopyEuropean Journal of Biochemistry, 1983
- Inhibition of calf thymus DNA polymerase α and of normal and cancer cell growth by butylanilinouracil and butylphenylguanineBiochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1982
- Acyclic analogues of purine and imidazole nucleosidesJournal of Heterocyclic Chemistry, 1982
- Hydroxyurea does not prevent synchronized G1 chinese hamster cells from entering the DNA synthetic periodBiochemical and Biophysical Research Communications, 1976