基于烯的强效和口服生物可用的EZH2抑制剂的不对称合成
Xinrong Tian1, Ken Newlander1, Louis LaFrance1
1GSK, Research and Development, 1250 South Collegeville Road, Collegeville, PA 19426, United States.
开发了EZH2抑制剂的关键中间体的高效合成. 这种方法可以通过进一步优化,发现强效的口服生物可用EZH2抑制剂.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
背景情况:
- 增强器Zeste同源2 (EZH2) 是一个关键的表观遗传调节器,涉及到各种癌症.
- 向EZH2为癌症治疗提供了一个有前途的治疗策略.
- 开发强效和选择性的EZH2抑制剂是一个活跃的研究领域.
研究的目的:
- 为了描述一种关键的中间体,6,7-dihydrothieno[3,2-c]pyridin-4(5H) -one (3) 的高效合成,用于EZH2抑制剂的开发.
- 报告发现新型,强效和口服生物可用EZH2抑制剂的发现,这些抑制剂来自中间体3.
主要方法:
- 一个1,1-异位化的基的化,以催化为催化剂.
- 苏苏基合,然后进行异醇碎片化,以甲基化硫烯.
- 两者同时进行酸降解和乳化,形成核心结构.
- 优化piperidine环替代物以产生最终的抑制剂.
主要成果:
- 取得了关键中间体 (3) 的成功和高效合成.
- 合成的中间体使得发现了强大的EZH2抑制剂 (例如25和26) 成为可能.
- 已识别的抑制剂显示出口服生物利用性.
结论:
- 开发的合成途径为访问EZH2抑制剂提供了一个有价值的平台.
- 对piperidine部分的进一步优化导致了有前途的候选药物的识别.
- 这项工作有助于推进针对EZH2.2的表观遗传疗法.
更多相关视频
06:34Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS
Published on: June 20, 2014
11:04Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine
Published on: June 13, 2022
相关概念视频
E2 Reaction: Stereochemistry and Regiochemistry
When a substrate with two different β hydrogens undergoes an E2 elimination, the presence of a strong base can yield two regioisomeric alkenes. The more-substituted alkene is the major...
Preparation and Reactions of Sulfides
Oxidation of Alkenes: Syn Dihydroxylation with Osmium Tetraoxide
E2 Reaction: Kinetics and Mechanism
E1 Reaction: Stereochemistry and Regiochemistry
Reduction of Alkenes: Asymmetric Catalytic Hydrogenation
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
