Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HTV-1 agents that target the viral nucleocapsid protein zinc fingers
Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HTV-1 agents that target the viral nucleocapsid protein zinc fingers
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DOI：
10.1021/jm9802517
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发表时间：
1999-01-14
影响因子：
7.3
通讯作者：
Appella, E
中科院分区：
文献类型：
--
作者：
Turpin, JA;Song, YS;Appella, E
人类免疫缺陷病毒1型（hhtv -1）的核衣壳p7蛋白（NCp7）锌指结构域由于其在病毒复制中的关键作用和突变不允许的性质而被开发为抗病毒靶点。根据我们对对称二硫苯酰胺（DIBAs； Rice等）的经验。Science 1995, 270,1194 -1197)，我们合成并评估了这些二聚体的变体，包括4,4'-和3,3'-二取代二苯基砜及其单体苯并异噻唑酮衍生物（BITA）。与二硫化物前体相比，BITAs通常表现出较低的抗病毒效力。通过- nhc (=O)-（酰胺）或- s - c (=O)-（硫酯）桥将卤代烷基连接到苯酰胺环上，形成了新的单体结构。酰胺连接的化合物通常缺乏抗病毒活性，而卤代烷酰硫酯和不含卤素的类似物经常表现出可接受的抗病毒效力，从而建立了硫酯苯酰胺本身作为一种新的抗hiv化学型。吡啶烷醇硫酯（PATEs）表现出优异的抗hiv -1活性，具有最小的细胞毒性和明显的水溶性。在对其他分子靶点进行测试时，PATEs被证明优先靶向NCp7 Zn指，从而确定硫酯苯酰胺，特别是PATEs，作为体内研究的新型NCp7 Zn指抑制剂。
Nucleocapsid p7 protein (NCp7) zinc finger domains of the human immunodeficiency virus type 1 (HTV-1) are being developed as antiviral targets due to their key roles in viral replication and their mutationally nonpermissive nature. On the basis of our experience with symmetrical disulfide benzamides (DIBAs; Rice et al. Science 1995, 270, 1194-1197), we synthesized and evaluated variants of these dimers, including sets of 4,4'- and 3,3'-disubstituted diphenyl sulfones and their monomeric benzisothiazolone derivatives (BITA). BITAs generally exhibited diminished antiviral potency when compared to their disulfide precursors. Novel, monomeric structures were created by linking haloalkanoyl groups to the benzamide ring through -NHC(=O)- (amide) or -S-C(=O)- (thiolester) bridges. Amide-linked compounds generally lacked antiviral activity, while haloalkanoyl thiolesters and non-halogen-bearing analogues frequently exhibited acceptable antiviral potency, thus establishing thiolester benzamides per se as a new anti-HIV chemotype. Pyridinioalkanoyl thiolesters (PATEs) exhibited superior anti-HIV-1 activity with minimal cellular toxicity and appreciable water solubility. PATEs were shown to preferentially target the NCp7 Zn finger when tested against other molecular targets, thus identifying thiolester benzamides, and PATEs in particular, as novel NCp7 Zn finger inhibitors for in vivo studies.