开发了14-epi-19-nortachysterol及其前所未有的结合配置,用于人类维生素D受体
Daisuke Sawada1, Yuya Tsukuda, Hiroshi Saito
1Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1, Suwarashi, Sagamihara, Kanagawa 252-5195, Japan.
Journal of the American Chemical Society
|April 20, 2011
概括
研究人员合成了新的14-epi-19-nortachysterol衍生物,发现它们是稳定的,并与维生素D受体 (VDR) 强烈结合. 这项研究标志着首次分离具有独特结合配置的稳定tachysterol类型.
科学领域:
- 合成有机化学 合成有机化学
- 内分泌学 在内分泌学.
- 结构生物学是结构生物学.
背景情况:
- 普雷维坦明D (3) 和其衍生物在平衡和细胞过程中至关重要.
- 已知高醇类型,但往往缺乏稳定性.
- 了解维生素D受体 (VDR) 配体相互作用是开发治疗剂的关键.
研究的目的:
- 为了合成和描述新型的14-epi-19-norprevitamin D(3) 衍生物.
- 研究这些新化合物的稳定性和VDR结合亲和力.
- 为了阐明这些类似物在人体VDR (hVDR) 结合体结合口袋中的结合配置.
主要方法:
- 化学合成的14-epi-19-norprevitamin D(3) 和随后的C6,7-cis/trans异构化.
- 由此产生的14-epi-19-nortachysterol衍生物的分离和净化.
- 使用已确定的生化分析评估化合物稳定性和与hVDR的结合亲和力.
- 结构分析以确定hVDR中的三烯配置.
主要成果:
- 成功合成了14-epi-19-nortachysterol衍生物. 这是一个成功的合成.
- 对合成的类似物有明显的稳定性和强大的VDR结合亲和力.
- 报告了第一个稳定的高胆固醇类型的首次隔离.
- 在hVDR联体结合口袋中观察到前所未有的结合配置 (C5,6-s-trans和C7,8-s-trans三烯).
结论:
- 已经合成了具有强大的VDR结合的稳定tachysterol类似物.
- 这些新型化合物在hVDR中表现出独特的结合模式,与天然的维生素D化合物不同.
- 这些发现为设计具有量身定制的结合性质的针对VDR的治疗方法开辟了新的途径.
相关概念视频
Role of Skin in Vitamin D Synthesis
The skin plays a crucial role in the synthesis of vitamin D, a vital nutrient for various physiological processes in the body. Vitamin D is unique because it can be synthesized in the skin through a series of chemical reactions triggered by exposure to ultraviolet B (UVB) radiation from sunlight.
The solar UV B rays (290-315 nm) are absorbed by the skin, and 7-dehydrocholesterol (provitamin D3) photolyzes it to previtamin D3, which undergoes a rapid transformation to vitamin D3(cholecalciferol).
The solar UV B rays (290-315 nm) are absorbed by the skin, and 7-dehydrocholesterol (provitamin D3) photolyzes it to previtamin D3, which undergoes a rapid transformation to vitamin D3(cholecalciferol).
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
The direct-acting...
Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Cholinergic Antagonists: Chemistry and Structure-Activity Relationship
Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic antagonists are called...
Cholesterol: Significance and Regulation
Although not a source of energy, cholesterol plays a significant role as a foundational structure for bile salts, steroid hormones, and vitamin D, as well as being a crucial component of plasma membranes. Approximately 15% of blood cholesterol is derived from our diet, with the remainder synthesized from acetyl CoA by the liver and intestines. Cholesterol is eliminated from the body through its conversion into bile salts, which are eventually discarded in the feces.
Considering cholesterol and...
Considering cholesterol and...
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
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...


