Boyle Nicholas A, Rajwanshi Vivek K, Prhavc Marija, Wang Guangyi, Fagan Patrick, Chen Fu, Ewing Gregory J, Brooks Jennifer L, Hurd Tiffany, Leeds Janet M, Bruice Thomas W, Cook P Dan
Research Laboratories, Biota, Inc., 2232 Rutherford Road, Carlsbad, California 92008, USA.
J Med Chem. 2005 Apr 7;48(7):2695-700. doi: 10.1021/jm040101y.
The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.
抗病毒2',3'-双脱氧核苷（ddNs）的三磷酸酯是抑制病毒DNA合成的活性化学物质。这种抑制作用包括将ddNMP掺入DNA并随后导致链终止。一种可行的抗病毒药物策略是使用能够完全绕过细胞磷酸化的核苷5'-三磷酸类似物。齐多夫定5'-α-R(P)-硼烷-β,γ-(二氟亚甲基)三磷酸酯（5'-αB-βγCF(2)TP）已被确定为HIV-1逆转录酶（HIV-1 RT）的有效抑制剂。这项工作旨在证实5'-αB-βγCF(2)TP是一种有用的通用三磷酸酯部分，并且能够使抗病毒ddNs对HIV-1 RT具有强效抑制作用。因此，通过一系列（一锅法）反应将10种ddNs转化为它们的5'-αB-βγCF(2)TPs：形成活性亚磷酸酯、形成环状三磷酸酯、硼氢化反应和水解反应。还探索了其他合成路线。所有测试的ddN 5'-αB-βγCF(2)TPs对HIV-1 RT的抑制水平与相应的ddNTPs基本相同。可以得出结论，就HIV-1 RT抑制和血清稳定性而言，5'-αB-βγCF(2)TP是一种通用且有前景的三磷酸酯类似物（P3M）。预计将5'-αB-βγCF(2)TP用作P3M部分将导致发现一类新型抗HIV药物。
