Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5A Pawinskiego St., 02-106 Warszawa, Poland.
Antiviral Res. 2011 Oct;92(1):57-63. doi: 10.1016/j.antiviral.2011.05.012. Epub 2011 Jun 6.
Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV-1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5'-triphosphates was investigated. The strongest inhibition was observed for K103N and Δ67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S4FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents.
使用改良的多步程序，制备了胸腺嘧啶 2'，3'-二脱氧-3'-氟核苷（FLT）及其 5'-单磷酸酯和 5'-三磷酸酯的各种硫代类似物。使用 deCIPhR 测定的复制表型格式，对 FLT 和 FLTMP 的硫代类似物进行了抗野生型和药物及多药耐药 HIV-1 株的评估，并在低细胞毒性下显示出对耐药 HIV-1 株的有效抑制。此外，还研究了合成的 5'-三磷酸酯对单和多种 HIV-1 突变体的重组耐药形式的逆转录酶的抑制作用。对于 K103N 和 Δ67 突变体，观察到最强的抑制作用，而对耐药株的最强抗 HIV-1 活性和最低细胞毒性则由 S4FLTMP 和 FLTMP 发挥，它们可被视为有潜力的抗 HIV/AIDS 药物。
