Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, Hamburg D-20146, Germany.
Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, Leuven B-3000, Belgium.
J Med Chem. 2023 Sep 14;66(17):12163-12184. doi: 10.1021/acs.jmedchem.3c00755. Epub 2023 Aug 30.
We report on the synthesis and evaluation of three different nucleotide prodrug systems: (i) nucleoside triphosphate analogues in which the γ-phosph(on)ate has two different lipophilic nonbioreversible alkyl residues with d4TDP as the released nucleotide analogue; (ii) nucleoside diphosphate analogues bearing a bioreversible and a stable β-alkyl group; or (iii) nucleoside diphosphate analogues bearing two nonhydrolysable lipophilic alkyl moieties. The delivery of d4TDP (for the triphosphate precursor) and d4TMP (for the diphosphate precursor) was demonstrated in CD4 T-lymphocyte CEM cell extracts as well as in phosphate buffer saline (PBS). In primer extension assay, we found that γ-dialkylated d4TTP derivatives and d4TDP were accepted as substrates by HIV-RT. Several of these compounds were observed to be extremely active against HIV-1/2 replication in HIV-infected cells. A more than 45,000-fold increase in the anti-HIV activity was detected for compound as compared to the parent d4T which results in a selectivity index value of 37,000.
（i）核苷三磷酸类似物，其中γ-磷酸（on）酯具有两个不同的亲脂性非生物可逆烷基残基，以 d4TDP 作为释放的核苷酸类似物；（ii）带有生物可逆和稳定的β-烷基的核苷二磷酸类似物；或（iii）带有两个不可水解的亲脂性烷基部分的核苷二磷酸类似物。在 CD4 T 淋巴细胞 CEM 细胞提取物以及磷酸盐缓冲盐水 (PBS) 中证明了 d4TDP（三磷酸前体）和 d4TMP（二磷酸前体）的递送。在引物延伸测定中，我们发现 γ-二烷基化的 d4TTP 衍生物和 d4TDP 可被 HIV-RT 接受为底物。在感染 HIV 的细胞中，这些化合物中的几种对 HIV-1/2 复制具有极高的活性。与母体 d4T 相比，化合物 的抗 HIV 活性增加了 45,000 多倍，导致选择性指数值为 37,000。
