3'-N,N-二甲基氨基-2',3'-二脱氧胸苷及其前药的合成、构效关系和抗病毒活性。

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

机构信息

Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India.

出版信息

Eur J Med Chem. 2010 Sep;45(9):3787-93. doi: 10.1016/j.ejmech.2010.05.028. Epub 2010 May 20.

A probable NRTI molecule, viz. 3'-N,N-dimethylamino-2',3'-dideoxythymidine (4) and its 5'-O-carboxyl ester prodrugs - 5'-(N-alpha-BOC-L-phenylalanyl)-3'-N,N-dimethylamino-2',3'-dideoxythymidine (5), 5'-L-phenylalanyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (6) and 5'-decanoyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC(50) value 0.03 microM (SI=8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT.

一种可能的 NRTI 分子，即 3'-N,N-二甲基氨基-2',3'-二脱氧胸苷（4）及其 5'-O-羧酸酯前药-5'-(N-α-BOC-L-苯丙氨酰基）-3'-N,N-二甲基氨基-2',3'-二脱氧胸苷（5）、5'-L-苯丙氨酰基-3'-N,N-二甲基氨基-2',3'-二脱氧胸苷（6）和 5'-癸酰基-3'-N,N-二甲基氨基-2',3'-二脱氧胸苷（7）已被合成并针对 HIV、HSV-1 和 2、副流感-3、水疱性口炎和其他几种病毒进行了筛选。化合物 6 在 Hela 和 HEL 细胞系中对 VSV 的 EC（50）值为 0.03 microM（SI=8），表现出良好的抗病毒活性。然而，先导化合物 4 及其衍生物 5、6 和 7 对 HIV-1 和其他病毒没有显著的活性。使用 DS 2.5 和 pymol 软件对 HIV-1 RT 进行分子对接研究表明，先导化合物 4 和 AZT 之间的相互作用模式存在明显差异。