基于氧二胺的基因素脱乙酶6抑制剂的设计,合成和生物活性
Si-Yuan Li1, Jiang-Shan Guo1, Ya-Jun Yang1
1Beijing Key Laboratory of Active Substance Discovery and Drug ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Journal of Asian natural products research
|June 30, 2024
概括
研究人员开发了针对阿尔茨海默氏病 (AD) 的新型基于氧胺的化合物,向组胺脱乙酶6 (HDAC6). 化合物12显示出强有力的和选择性的HDAC6抑制,具有有前途的体外活性,表明其作为AD治疗的潜力.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 生物化学 生物化学
背景情况:
- 阿尔茨海默病 (AD) 是一种进展性神经退行性疾病.
- 希斯脱乙酶6 (HDAC6) 参与AD病变发生,是潜在的治疗点.
研究的目的:
- 设计,合成和评估基于氧基胺的新型化合物作为选择性HDAC6抑制剂,用于潜在的阿尔茨海默病治疗.
- 为了识别具有高强度,选择性和良好的体外特征的化合物.
主要方法:
- 一系列含有多种链接部分的氧基胺衍生物的合成.
- 在体外酶分析以确定HDAC6抑制活性和对HDAC1.1的选择性.
- 细胞毒性测定和反氧化物 (H2O2) 活性评估.
主要成果:
- 化合物12,具有基链接剂,成为一种高度强效和选择性的HDAC6抑制剂.
- 化合物12对HDAC6的IC50为6.2nM,与HDAC1.1相比,具有超过200倍的选择性.
- 与其他衍生物相比,这种化合物在体外显示出降低细胞毒性和增强抗H2O2活性.
结论:
- 化合物12是新型HDAC6抑制剂的有希望的主要候选者.
- 这些发现支持针对阿尔茨海默病治疗的HDAC6的潜力.
相关概念视频
Spreading of Chromatin Modifications
8.2K
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer...
Writers
The writer...
8.2K
Histone Modification
3.4K
3.4K
Structure-Activity Relationships and Drug Design
697
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
697
Eukaryotic Transcription Inhibitors
9.8K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
9.8K
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
552
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
552


