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作为模板结构的N-甲基化循环五氨酸.
Jayanta Chatterjee1, Dale Mierke, Horst Kessler
1Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany.
Journal of the American Chemical Society
|November 23, 2006
概括
循环的N-甲基化增强了生物可用性,并允许结构控制. 这项研究合成和分析了N-甲基化,确定了七种具有稳定的单一构造的药物设计.
科学领域:
- 药用化学 医学化学
- 类化学 类化学
- 结构生物学 结构生物学
背景情况:
- 的N-甲基化通过改变灵活性和脂友性来调节活性,选择性和生物可用性 (ADMET概况).
- 形状受约束的循环对于药物设计和理解生物系统是有价值的.
研究的目的:
- 合成和描述一个N-甲基化循环的库,以识别形态稳定的结构.
- 为合理的药物设计和医疗重要系统的空间查建立模板.
主要方法:
- 合成30个N-甲基化循环的库,其序列为cyclo(-D-Ala-L-Ala4-).
- 核磁共振 (NMR) 分析以确定形状稳定性.
- 在明确的DMSO中进行距离几何和分子动力学模拟,以进行结构改进.
主要成果:
- 在30种合成的N-甲基化中,有7种表现出单个,稳定的构造 (>98%的人口).
- 这些结构受约束的详细结构特征得到了阐明.
- 这项研究为理解N-甲基化循环的结构-活性关系提供了基础.
结论:
- N-甲基化是一种有效的策略,用于实现循环的构造约束.
- 鉴定到的稳定形状可以作为设计新疗法的模板.
- 这项工作有助于对基于类药物的生物活性构成进行空间选.
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