构成,构成偏好和构成交换的N'-替代N-acylguanidines:分子间相互作用是关键
Roland Kleinmaier1, Max Keller, Patrick Igel
1Institut für Organische Chemie, Universität Regensburg, Germany.
Journal of the American Chemical Society
|August 12, 2010
概括
乙瓜尼丁,瓜尼丁的较少基本的生物异构体,无论环境如何,都表现出一致的构造. 分子间相互作用决定了它们的形状偏好和汇率,有助于药物设计.
科学领域:
- 药用化学 医学化学
- 有机化学 有机化学
- 结构生物学 结构生物学
背景情况:
- 关尼丁和基关尼丁的部分在生物活性化合物中至关重要.
- 乙guanidines作为guanidines的生物异构体,提供改善的药理动力学和药理动力学特性,特别是作为G蛋白结合受体 (GPCR) 配体.
- 对乙瓜因丁增强的配体受体相互作用及其构造偏好的分子基础仍然不太清楚,现有数据有限且相互矛盾.
研究的目的:
- 为了研究单基化酸瓜因丁的构造,构造偏好和构造交换.
- 阐明阳离子,微溶解和替代剂变异对乙烯基胺构造的影响.
- 建立对溶液和固体状态中的乙基胺构造性行为的一致的理解.
主要方法:
- 核磁共振 (NMR) 光谱学被用来研究四种无质子和七种质子单基化基甲基胺.
- 这项研究涉及各种离子,双酸针,以及用二甲基硫化物微溶解.
- 分析了水晶结构,并与溶液状态的形状偏好进行了比较.
主要成果:
- 在所有测试的化合物,离子和溶剂中,在八种可能的乙瓜因丁构造中,只有两个被始终检测到.
- 分子间相互作用的强度和数量被确定为形状偏好和汇率的关键决定因素.
- 观察到的溶液状态形状偏好得到了三种晶体结构的证实,包括强大的GPCR配体.
结论:
- 单基化乙瓜尼丁表现出非常一致的形状偏好.
- 分子间相互作用在调节酸氨的构成和动态方面发挥着至关重要的作用.
- 这些发现为了解作用机制和合理设计基于乙瓜尼丁的新型治疗方法提供了基础.
相关概念视频
01:11Nucleophilic Aromatic Substitution: Elimination–Addition
Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is confirmed through isotopic...
02:30Stability of Substituted Cyclohexanes
This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
00:52¹H NMR of Conformationally Flexible Molecules: Temporal Resolution
At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
01:19Structure of Amines
The hybridized nitrogen atom in amines possesses a lone pair of electrons and is bound to three substituents with a bond angle of around 108°, which is less than the tetrahedral angle of 109.5°. However, the C–N–H bond angle is slightly larger at 112°, with a carbon–nitrogen bond length of 147 pm. This carbon–nitrogen bond length of of amines is longer than the carbon–oxygen bond of alcohols (143 pm) but shorter than alkanes’ carbon–carbon bond (154 pm). These aspects are illustrated in Figure...
01:30Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)
Nucleophilic substitution in aromatic compounds is feasible in substrates bearing strong electron-withdrawing substituents positioned ortho or para to the leaving group. The reaction proceeds via two steps: the addition of the nucleophile and the elimination of the leaving group.
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between the...
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between the...
01:14Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN1
Treating arylamines with nitrous acid gives aryldiazonium salts that are effective substrates in nucleophilic aromatic substitution reactions. The diazonio group in these salts can be easily displaced by different nucleophiles, yielding a wide variety of substituted benzenes. The leaving group departs as nitrogen gas, and this easy elimination is the driving force for the substitution reaction.
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo, or cyano...
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo, or cyano...