循环伊米德立体异构体对大脑细胞依赖活动的贡献
Yuka Amako1, Saki Ichikawa1, Hannah C Lloyd1
1Department of Chemistry and Chemical Biology, Harvard University Cambridge MA 02138 USA cwoo@chemistry.harvard.edu.
Chemical science
|May 30, 2025
概括
奇拉性会影响cereblon (CRBN) 如何结合像thalidomide这样的循环 imide. 虽然 (S) 立体同位素是首选的,但 (R) 立体同位素也可以参与CRBN,影响药物降解和治疗结果.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药用化学 医学化学
背景情况:
- thalidomide及其衍生物是通过激活大脑蛋白 (CRBN) E3结合酶而起作用的关键治疗药物.
- 这些药物具有性中心,立体化学可以显著影响生物活性和治疗疗效.
- 了解性在CRBN介导的蛋白质降解中的作用对于药物开发至关重要.
研究的目的:
- 系统地研究循环胺基的立体异构体对CRBN参与,三元复合体形成和蛋白质降解的影响.
- 评估不同循环伊米德化合物的种族化动力学.
- 阐明 (S) 和 (R) 两种立体异构体如何促进CRBN依赖的细胞活动.
主要方法:
- 在小分子,和蛋白质中对循环化胺的系统检查.
- 在非酶条件下评估种族化.
- 在体外分析CRBN参与和三元复合体形成.
- 在细胞模型中评估蛋白质降解结果.
主要成果:
- 在CRBN的thalidomide结合域优先结合循环imides的 (S) -立体异构体.
- 然而, (R) 立体同位素也可以与CRBN结合,有时会增强或阻碍目标参与和降解.
- 在非酶条件下,列纳利多米德衍生物呈现出快速的种族化 (t50%ee = 4-5 h).
- (S) 立体同位素是主要的配体,但 (R) 立体同位素可以促进CRBN依赖的细胞活动.
结论:
- 立体化学是周期性伊米德和CRBN之间的相互作用的关键因素.
- 虽然 (S) - 立体异构体是主要的结合剂,但 (R) - 立体异构体在CRBN介导的过程中具有功能相关性.
- 这些发现对设计和应用针对CRBN途径的奇拉药物有影响.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
相关概念视频
02:33Stereoisomerism of Cyclic Compounds
9.3K
In this lesson, we delve into the role of ring conformation and its stability, which determines the spatial arrangement and, consequently, the molecular symmetry and stereoisomerism of cyclic compounds. 1,2-Dimethylcyclohexane is used as a case study to evaluate the possible number of stereoisomers. Here, given the multiple (n = 2) chiral centers, there are 2n = 4 possible configurations that lack a plane of symmetry, as the ring skeleton exists in a non-planar chair conformation. In addition,...
9.3K
02:05Prochirality
4.0K
The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
4.0K
01:29Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
4.8K
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
4.8K
02:32Stereoisomers
14.0K
On the basis of mirror symmetry, stereoisomers of an organic molecule can be further classified into diastereomers and enantiomers. Diastereomers are stereoisomers that are not mirror images of each other. Substituted alkenes, such as the cis and trans isomers of 2-butene, are diastereomers, as these molecules exhibit different spatial orientations of their constituent atoms, are not mirror images of each other, and do not interconvert. Here, the interconversion is suppressed due to...
14.0K
02:37Disubstituted Cyclohexanes: cis-trans Isomerism
12.4K
Depending upon the different spatial orientation of the substituents, the disubstituted cycloalkanes exhibit two types of stereoisomers. The cis isomers have the substituents on the same side of the ring, whereas the trans isomers have the substituents on the opposite sides. These stereoisomers exhibit different physical properties and cannot be interconverted without breaking the carbon-carbon bonds.
In cyclohexane, the substituents can occupy different positions generating distinct isomers....
In cyclohexane, the substituents can occupy different positions generating distinct isomers....
12.4K
02:52Stereoisomerism
12.5K
Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
12.5K