Boyle Nicholas A, Fagan Patrick, Brooks Jennifer L, Prhavc Marija, Lambert John, Cook P Dan
Research Laboratories, Biota Inc., Carlsbad, California, USA.
Nucleosides Nucleotides Nucleic Acids. 2005;24(10-12):1651-64. doi: 10.1080/15257770500267055.
Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.
核苷类逆转录酶抑制剂（NRTIs）是前体药物，需要经过三步细胞内磷酸化才能产生其相应的、具有生物活性的核苷三磷酸。为了规避这种通常效率不高的磷酸化级联反应，一种可行的方法是以稳定的核苷三磷酸类似物的形式直接提供活性物质。我们之前已经表明，这样一种类似物，即5'-α-Rp-硼烷-β,γ-（二氟亚甲基）三磷酸（5'-αBCF2TP）是一种通用的三磷酸类似物，具有生物稳定性，并且可以使抗病毒双脱氧核苷对HIV-1逆转录酶具有强大的抑制活性。在此，我们报告了几种具有非桥连αP-硫代（5'-αSCF2TP）或α-P-硒代（5'-αSeCF2TP）修饰的双脱氧核苷5'-α-修饰-β,γ-（二氟亚甲基）三磷酸类似物的合成及其对HIV-1逆转录酶的活性。一种化合物，即齐多夫定-5'-α-P-硒代-β,γ-（二氟亚甲基）三磷酸（非对映异构体I），被鉴定为HIV-1逆转录酶的强效抑制剂（Ki = 64 nM），这是关于带有α-P-硒代修饰的核苷酸的HIV-1逆转录酶抑制数据的首次报道。这些三磷酸类似物可能在酶机制研究中有用，并且在耐药性和聚合酶选择性方面可能具有有趣的特性。
