Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant--target interactions.
Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant--target interactions.
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DOI：
10.1021/tx2003257
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发表时间：
2012-02-20
影响因子：
4.1
通讯作者：
Barber DS
中科院分区：
文献类型：
--
作者：
Lopachin RM;Gavin T;Decaprio A;Barber DS
许多化学毒物和/或其活性代谢物是亲电试剂，通过与生物大分子上的亲核靶标形成共价键而引起细胞损伤。然而，亲核试剂和亲电试剂之间的共价反应是有区别的，因为这些相互作用有很大程度的选择性。在过去的几十年里，硬、软、酸、碱（HSAB）理论已被证明是预测这类反应结果的有用工具。这个概念利用固有的电子极化特性来定义，例如，反应的亲电试剂和亲核试剂是硬的还是软的。这些HSAB定义已成功地应用于生物系统中化学诱导的毒性。因此，根据这一原理，有毒亲电试剂优先与硬度或柔软度相似的生物靶标发生反应。异种亲电试剂的软/硬分类在识别可能的生物靶点和毒性的分子机制方面具有明显的实用性。本展望的目的是在毒理学框架内讨论亲电试剂和亲核试剂的HSAB理论。原则上，共价键的形成可以用它们最外层或前沿轨道的性质来描述。由于大多数化学物质的这些轨道能量可以用量子力学模型计算，因此可以量化亲电试剂或亲核试剂的相对柔软度（σ）或硬度（η），并随后将这些信息转化为有用的反应性指标。这种原子水平的信息可以提供深入了解确证实验室研究的设计，从而帮助研究人员辨别相应的分子位点和毒性作用的机制。HSAB参数的使用也有助于开发和鉴定潜在的亲核细胞保护剂，可以清除有毒的亲电试剂。显然，描述分子位点和毒性作用机制的困难任务可以通过应用这种定量方法来促进。
Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macromolecules. Covalent reactions between nucleophilic and electrophilic reagents are however discriminatory, since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acid and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in discerning plausible biological targets and molecular mechanisms of toxicity. The purpose of this Perspective is to discuss the HSAB theory of electrophiles and nucleophiles within a toxicological framework. In principle, covalent bond formation can be described by using the properties of their outermost or frontier orbitals. Because these orbital energies for most chemicals can be calculated using quantum mechanical models, it is possible to quantify the relative softness (σ) or hardness (η) of electrophiles or nucleophiles and to subsequently convert this information into useful indices of reactivity. This atomic level information can provide insight into the design of corroborative laboratory research and thereby help investigators discern corresponding molecular sites and mechanisms of toxicant action. The use of HSAB parameters has also been instrumental in the development and identification of potential nucleophilic cytoprotectants that can scavenge toxic electrophiles. Clearly, the difficult task of delineating molecular sites and mechanisms of toxicant action can be facilitated by the application of this quantitative approach.
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影响因子：
4.1
作者：
Cai, Jian;Bhatnagar, Aruni;Pierce, William M., Jr.
通讯作者：
Pierce, William M., Jr.
DOI：
10.1016/j.bbalip.2010.02.005
发表时间：
2010-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Butterfield DA;Bader Lange ML;Sultana R
通讯作者：
Sultana R
影响因子：
2.3
作者：
Aldini, Giancarlo;Gamberoni, Luca;Carini, Marina
通讯作者：
Carini, Marina
影响因子：
3.8
作者：
GREEN, MA;EGLE, JL
通讯作者：
EGLE, JL
影响因子：
2.3
作者：
Aldini, G;Dalle-Donne, I;Carini, M
通讯作者：
Carini, M