You Youngsu, Kim Hee Sun, Park Jung Woo, Keum Gyochang, Jang Sung Key, Kim B Moon
Department of Chemistry, College of Natural Sciences, Seoul National University Seoul 08826 South Korea
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology Pohang 37673 South Korea.
RSC Adv. 2018 Sep 12;8(55):31803-31821. doi: 10.1039/c8ra05471a. eCollection 2018 Sep 5.
Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.
设计并合成了具有取代联芳基硫酸酯核心结构的超强效新型丙型肝炎病毒（HCV）非结构5A（NS5A）。基于先前报道的具有联芳基硫酸酯核心结构的新型HCV NS5A抑制剂，其对HCV 1b型和2a型基因型显示出两位数皮摩尔的半数最大有效浓度（EC）值，探索了配备含有不同取代芳基的硫酸酯核心结构的新型抑制剂。在本研究中，利用了芳基磺酰氟与芳基硅醚之间高效、化学选择性的偶联反应，即硫（VI）氟交换（SuFEx）反应。在基于SuFEx化学制备的抑制剂中，化合物14、15和29对GT-1b显示出两位数皮摩尔的EC值，对HCV GT-2a毒株显示出个位数或亚纳摩尔活性。还合成了在硫酸酯核心结构两侧含有咪唑和酰胺部分的不对称抑制剂。此外，使用相同的合成方法制备了用于标记的靶向NS5A蛋白的生物素化探针。
