Tramontano E, Marongiu M E, de Montis A, Loi A G, Artico M, Massa S, Mai A, la Colla P
Dipartimento di Biologia Sperimentale, Università di Cagliari, Italy.
New Microbiol. 1994 Oct;17(4):269-79.
Novel 3,4-dihydro-6-benzyl-4-oxopyrimidines (DABOs), variously substituted at both the C-2 and C-5 positions of the pyrimidine ring, proved to be specific inhibitors of the human immunodeficiency virus type 1 (HIV-1) in vitro. Some compounds showed potency at micromolar doses, no cytotoxicity at the maximum testable doses and selectivity indexes comparable to that of 2'-3'-dideoxyinosine (ddI). Mode of action studies suggested that DABOs interfered with a step of the virus multiplication cycle following adsorption and preceding integration. Enzyme assays indicated that DABOs targeted HIV-1 reverse transcriptase: they inhibited the RNA-dependent DNA polymerase activity in a template-dependent manner and, to a lesser extent, the DNA-dependent DNA polymerase activity. No inhibition of the RNase-H associated activity was observed. When DABOs were assayed in combination with 3'-azido-3'-dideoxythymidine (AZT) or ddI against HIV-1 in cell cultures, a slightly synergistic inhibitory effect was observed. The combination of DABO 546 and AZTTP in enzyme assays showed that the two compounds were kinetically mutually exclusive.
新型3,4 - 二氢 - 6 - 苄基 - 4 - 氧代嘧啶（DABOs）在嘧啶环的C - 2和C - 5位有不同取代，在体外被证明是人类免疫缺陷病毒1型（HIV - 1）的特异性抑制剂。一些化合物在微摩尔剂量下显示出效力，在最大可测试剂量下无细胞毒性，且选择性指数与2',3'-双脱氧肌苷（ddI）相当。作用模式研究表明，DABOs在病毒吸附后、整合前干扰病毒增殖周期的一个步骤。酶分析表明，DABOs靶向HIV - 1逆转录酶：它们以模板依赖的方式抑制RNA依赖性DNA聚合酶活性，并在较小程度上抑制DNA依赖性DNA聚合酶活性。未观察到对RNase - H相关活性的抑制。当在细胞培养物中针对HIV - 1将DABOs与3'-叠氮 - 3'-脱氧胸苷（AZT）或ddI联合测定时，观察到轻微的协同抑制作用。在酶分析中DABO 546与AZTTP的组合表明这两种化合物在动力学上相互排斥。
