康达里丁的反应性无水化物对生物氨基的共价结合
Yaya Fan1, Lin Chen1, Qiuyi Jing1
1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education (Y.F., L.C., Q.J., X.L., H.P., C.F., F.S.), Department of Clinical Pharmacy (H.P.), and Department of Pharmaceutical Analysis (J.Z.), Zunyi Medical University, Zunyi, China; and Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (C.F.).
概括
康达里丁无水化物与生物胺结合,形成胺和胺结合物. 这种非酶反应在试验室和小鼠中观察到,澄清了利丁毒性机制.
科学领域:
- 化学生物学 化学生物学
- 毒理学 毒理学 毒理学
- 有机化学 有机化学
背景情况:
- 昆虫产生的化物康达里丁 (Cantharidin) 用作药物,但具有高度毒性.
- 利丁中毒的机制尚未完全理解.
- 坎塔里丁的无水化组表明了与生物核友的潜在反应性.
研究的目的:
- 为了研究利丁与生物胺的化学反应性.
- 描述cantharidin和生物胺之间形成的添加物.
- 阐明非酶反应在利丁毒性中的作用.
主要方法:
- 在生理条件下,用氨基酸,和含氨酸的化合物化康塔里丁.
- 使用高分辨率质谱法对结合物进行表征.
- 使用14N/15N和79Br/81Br同位素特征和核磁共振 (NMR) 光谱学确认结合结构.
- 在小鼠肝脏和尿液中检测结合物,并分析蛋白质修饰.
主要成果:
- 康塔里丁通过非酶的共价结合,与生物胺形成了胺和胺结合物.
- 同位素标记和NMR证实了这些胺和胺结合物的结构.
- 在小鼠肝脏和尿液中检测到康达里丁-氨酸合物.
- 抑制细胞染色体P450酶增加了尿中利丁合物,这表明非酶性途径是显著的.
结论:
- 康达里丁的无水化部分很容易与生物氨基的初级氨基群进行非酶的反应.
- 胺基和胺基合物的形成有助于了解坎塔里丁的毒理学特征.
- 这项研究强调了非酶反应在利丁中毒中的重要性.
相关概念视频
01:26Physical Properties of Amines
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Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
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01:19Amines to Amides: Acylation of Amines
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Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
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01:19Reactions of Acid Anhydrides
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The reactions of acid anhydrides are analogous to the reactions of acid chlorides and proceed via a nucleophilic acyl substitution. They only differ in the identity of the leaving group. During an acid chloride reaction, the leaving group is a chloride ion, and the by-product is hydrochloric acid. However, in an acid anhydride reaction, the leaving group is a carboxylate ion, and the by-product is a carboxylic acid.
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01:38Preparation of Amines: Reductive Amination of Aldehydes and Ketones
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Carbonyl compounds and primary amines undergo reductive amination first to produce imines, followed by secondary amines in the same reaction mixture, using selective reducing agents like sodium cyanoborohydride or sodium triacetoxyborohydride. Reductive amination produces different degrees of substitution of amines depending on the starting amine substrate.
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01:07Preparation of Acid Anhydrides
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One of the methods for preparing symmetrical or unsymmetrical acid anhydrides involves the treatment of acid chlorides with the sodium salt of carboxylic acids. The reaction proceeds via a nucleophilic acyl substitution.
The carboxylate ion acts as a nucleophile that attacks the carbonyl carbon of the acid chloride to form a tetrahedral intermediate. Subsequently, the re-formation of the carbonyl group with the loss of the chloride ion as a leaving group leads to the formation of an acid...
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01:29Preparation of Amides
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Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
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