Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies

You Youngsu; Kim Hee Sun; Park Jung Woo; Keum Gyochang; Jang Sung Key; Kim B. Moon

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Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies

机译：硫（VI）氟化物交换作为合成硫酸二硫酸酯核心衍生物作为有效丙型肝炎病毒NS5A抑制剂及其结构 - 活性关系研究的关键反应

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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 (EC50) 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 EC50 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.

机译：设计并合成了极其有效的新型丙型肝炎病毒（HCV）非结构5A（NS5A）具有取代的硫酸铝核心结构。基于先前报道的新型HCV NS5A抑制剂，其具有硫酸二硫酸盐核心结构的硫胺核心结构，其对HCV基因型1B和2A的两位PICOMOLAR半最大有效浓度（EC50）值，所述新抑制剂配备含有含有多样取代的芳基的硫酸盐核心结构探索了。在这项研究中，芳基磺酰氟和之间高效，化学选择性偶联反应的芳甲硅烷基醚，被称为硫（VI），氟化交换（SuFEx）反应，进行了利用。在基于Sufex化学制备的抑制剂中，化合物14,15和29表现出对GT-1B的两位PICOMOLAR EC50值，以及针对HCV GT-2A菌株的单位数或亚纳米粗酚活性。还合成了含有咪唑和酰胺部分的非对称抑制剂，也合成了硫酸盐核心结构的每一侧。另外，制备使用相同的合成方法标记靶向NS5A蛋白的生物素化探针。

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《RSC Advances》 |2018年第55期|共19页
作者
You Youngsu; Kim Hee Sun; Park Jung Woo; Keum Gyochang; Jang Sung Key; Kim B. Moon;
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作者单位

Seoul Natl Univ Coll Nat Sci Dept Chem Seoul 08826 South Korea;

Pohang Univ Sci &

Technol Div Integrat Biosci &

Biotechnol Pohang 37673 South Korea;

KISTI Supercomp Modeling &

Simulat Ctr Div Data Anal 245 Daehak Ro Daejeon 34141 South Korea;

KIST Ctr Neuromed Brain Sci Inst Hwarangno 14 Gil 5 Seoul 02455 South Korea;

Pohang Univ Sci &

Technol Dept Life Sci Pohang 37673 South Korea;

Seoul Natl Univ Coll Nat Sci Dept Chem Seoul 08826 South Korea;

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正文语种 eng
中图分类化学;
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1. Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies [J] . You Youngsu, Kim Hee Sun, Park Jung Woo, RSC Advances . 2018,第55期

机译：硫（VI）氟化物交换作为合成硫酸二硫酸酯核心衍生物作为有效丙型肝炎病毒NS5A抑制剂及其结构 - 活性关系研究的关键反应
2. Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure–activity relationship studies [J] . Youngsu You, Hee Sun Kim, Jung Woo Park, RSC Advances . 2018,第55期

机译：氟化硫（vi）交换是合成作为有效丙型肝炎病毒NS5A抑制剂的硫酸联芳基酯核心衍生物的关键反应及其构效关系研究
3. Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109 [J] . Hirashima S, Suzuki T, Ishida T, Journal of Medicinal Chemistry . 2006,第15期

机译：带有取代联苯的苯并咪唑衍生物作为丙型肝炎病毒NS5B RNA依赖性RNA聚合酶抑制剂：结构与活性的关系研究以及强效和高度选择性抑制剂JTK-109的鉴定
4. Discovering Relationship between Hepatitis C Virus NS5A Protein and Interferon/Ribavirin Therapy [C] . Saori Kawasaki, Tu Bao Ho, Tatsuo Kanda, International Conference on Knowledge, Information, and Creativity Support Systems . 2011

机译：发现丙型肝炎病毒NS5A蛋白与干扰素/利巴韦林治疗的关系
5. P27 as a molecular target for cancer therapeutics: Discovering small molecule inhibitors of p27 proteolysis and structure-activity relationship and mechanistic studies of largazole, a potent inhibitor of histone deacetylase . [D] . Ungermannova, Dana. 2010

机译：P27作为癌症治疗的分子靶标：发现p27蛋白水解和结构活性关系的小分子抑制剂以及组蛋白脱乙酰基酶的有效抑制剂largazole的机理研究。
6. Potent Hepatitis C Virus NS5A Inhibitors Containinga Benzidine Core [O] . Il Hak Bae, Jin Kyu Choi, Chieyeon Chough, 2014

机译：含有强效丙型肝炎病毒NS5A抑制剂联苯胺核
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机译：N-（3-氧代-3,4-二氢-2H-苯并（1,4）恶氨酸-7-羰基）胍衍生物作为有效的NA / H兑换抑制剂的设计，合成和定量结构 - 活性研究。

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies

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