5-卤代-6-甲氧基（或叠氮基）-5,6-二氢-3'-氟-3'-脱氧胸苷非对映异构体的合成及其抗病毒（HIV-1、HBV）活性。3'-氟-3'-脱氧胸苷的潜在前体药物。

Synthesis and antiviral (HIV-1, HBV) activities of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidine diastereomers. Potential prodrugs to 3'-fluoro-3'-deoxythymidine.

作者信息

Kumar R, Wang L, Wiebe L I, Knaus E E

机构信息

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.

出版信息

J Med Chem. 1994 Oct 14;37(21):3554-60. doi: 10.1021/jm00047a013.

DOI:10.1021/jm00047a013

PMID:7932583

Abstract

A new class of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'- deoxythymidines (4-13) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-fluoro-3'-deoxythymidine (FLT), were designed to have properties which would enhance their duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, N3) to the 5,6-olefinic bond of FLT. These 5-halo-6-methoxy-5,6-dihydro derivatives are more lipophilic (P = 1.5-5.15 range) than the parent compound FLT (P = 0.5). Regeneration of the 5,6-olefinic bond to give FLT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, was dependent on the nature of the 5-halo substituent (I > Br > Cl). The ability of these 5-halo-6-methoxy(or azido)-5,6- dihydro compounds (4-13) to protect CEM cells against HIV-induced cytopathogenicity was evaluated. The C-5 halo substituent was a determinant of anti-HIV-1 activity where the approximately equipotent 5-iodo and 5-bromo were generally more potent than the 5-chloro derivatives of FLT. Compounds having the (5S,6S)-configuration were more potent than the corresponding (5R,6R)-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,6R)-5-Br,6-OMe (4), (5S,6S)-5-Br,6-OMe (5), and (5S,6S)-5-I,6-OMe (10) derivatives of FLT, exhibited comparable activities to the reference drugs AZT and FLT. Although (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine (4) inhibited hepatitis B virus replication at a 5-6-fold higher concentration (EC50) than the reference drug 2',3'-dideoxycytidine (DDC), it was 3-5-fold less cytotoxic (CC50) than DDC.

摘要

一类新型的5-卤代-6-甲氧基（或叠氮基）-5,6-二氢-3'-氟-3'-脱氧胸苷（4-13）作为潜在的抗艾滋病药物进行了研究。这些5,6-二氢衍生物也是3'-氟-3'-脱氧胸苷（FLT）的潜在前药，其设计目的是具有能延长其作用持续时间、亲脂性以及向中枢神经系统脑部递送的特性。5-卤代-6-甲氧基（或叠氮基）-5,6-二氢-3'-氟-3'-脱氧胸苷在C-5和C-6位构型不同，通过将XR（X = Br、Cl、I；R = OMe、N3）区域特异性加成到FLT的5,6-烯键上合成。这些5-卤代-6-甲氧基-5,6-二氢衍生物比母体化合物FLT（P = 0.5）更具亲脂性（P在1.5 - 5.15范围内）。当5-卤代-6-甲氧基-5,6-二氢化合物与谷胱甘肽一起孵育时，5,6-烯键再生生成FLT取决于5-卤代取代基的性质（I > Br > Cl）。评估了这些5-卤代-6-甲氧基（或叠氮基）-5,6-二氢化合物（4-13）保护CEM细胞免受HIV诱导的细胞病变效应的能力。C-5卤代取代基是抗HIV-1活性的决定因素，其中5-碘代和5-溴代的活性大致相当，通常比FLT的5-氯代衍生物更有效。具有（5S,6S）-构型的化合物比相应的（5R,6R）-非对映异构体更有效。最有效的抗HIV-1药物，包括FLT的（5R,6R）-5-溴-6-甲氧基（4）、（5S,6S）-5-溴-6-甲氧基（5）和（5S,6S）-5-碘-6-甲氧基（10）衍生物，表现出与参考药物齐多夫定（AZT）和FLT相当的活性。尽管（5R,6R）-5-溴-6-甲氧基-5,6-二氢-3'-氟-3'-脱氧胸苷（4）抑制乙型肝炎病毒复制的浓度（EC50）比参考药物2',3'-二脱氧胞苷（DDC）高5 - 6倍，但它的细胞毒性（CC50）比DDC低3 - 5倍。