可调节的甲烯胺用于共价联结体定向释放化学
Rambabu N Reddi1, Efrat Resnick1, Adi Rogel1
1Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 7610001, Israel.
Journal of the American Chemical Society
|March 25, 2021
概括
研究人员开发了α- 替代甲胺,这是向共价抑制剂的新型电友类. 这些化合物具有可调节的反应性,并可用于药物发现和化学生物学应用的"启动"探针.
科学领域:
- 医学化学
- 化学生物学
- 药物发现
背景情况:
- 有针对性的共价抑制剂对于药物开发和化学探测至关重要.
- 有限数量的电友适合设计有效的共价抑制剂.
- 现有的烯胺电可能缺乏所需的反应性或选择性.
研究的目的:
- 引入α替代甲胺作为向共价抑制剂的新类电友.
- 研究这些新型电友的反应性和可调性.
- 展示它们在开发"启动"探测器和促进药物发现屏幕中的应用.
主要方法:
- 合成和表征异位α替代甲胺.
- 对醇的反应性和与离开组特性 (pKa/pKb) 的相关性进行评估.
- 用于蛋白质标记,激酶测试和细胞测试的修改后的ibrutinib类型.
- 共价联体导向释放 (CoLDR) 启动探针 (光和化学发光) 的开发.
主要成果:
- 异α替代甲胺通过结合式添加-消除机制表现出可调节的醇反应性.
- 经过修改的易布鲁替尼类药物表现出可比的效力,具有更好的选择性.
- 对BTK,EGFR和K-RasG12C成功开发了COLDR探针.
- 一个BTK CoLDR化学发光探测器为高通量屏幕的抑制剂提供了便利.
结论:
- 用α替代的甲基胺为向共价抑制剂设计提供了一个多功能新平台.
- 它们的可调节反应性和形成"启动"探针的能力提高了它们在化学生物学中的实用性.
- 这种方法提高了选择性,并为药物发现提供了新的选策略.
相关概念视频
Metal-Ligand Bonds
22.7K
The hemoglobin in the blood, the chlorophyll in green plants, vitamin B-12, and the catalyst used in the manufacture of polyethylene all contain coordination compounds. Ions of the metals, especially the transition metals, are likely to form complexes.
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
22.7K
Complexometric Titration: Ligands
1.6K
Different monodentate and polydentate ligands are used as complexing agents in complexometric titration reactions. The formation of complexes by mono- and bidentate ligands involves two or more intermediate steps, limiting their use as complexing agents. In comparison, polydentate ligands can form complexes with metal ions in a single-step process, facilitating sharper end points. This means polydentate ligands, such as amino carboxylic acid derivatives, are most commonly employed in...
1.6K
EDTA: Chemistry and Properties
2.6K
Polydentate ligands are most widely used in complexometric titrations because they form more stable complexes with the metal ions than mono- or bidentate ligands due to the chelate effect. Examples of polydentate ligands are ethylenediaminetetraacetic acid (EDTA), crown ethers, and cryptands. The most important feature of optimal polydentate ligands is the ability to form 1:1 complexes in a single-step process. Amino carboxylic acid derivatives are frequently used as complexing agents. EDTA is...
2.6K
Olefin Metathesis Polymerization: Acyclic Diene Metathesis (ADMET)
2.0K
Acyclic diene metathesis polymerization or ADMET polymerization involves cross-metathesis of terminal dienes, such as 1,8-nonadiene, to give linear unsaturated polymer and ethylene. As ADMET is a reversible process, the formed ethylene gas must be removed from the reaction mixture to complete the polymerization process.
Similar to cross-metathesis, ADMET also involves the formation of metallacyclobutane intermediate by [2+2] cycloaddition of one of the double bonds of a terminal diene with...
Similar to cross-metathesis, ADMET also involves the formation of metallacyclobutane intermediate by [2+2] cycloaddition of one of the double bonds of a terminal diene with...
2.0K


