Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase
Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase
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DOI：
10.1248/cpb.49.1066
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发表时间：
2001-09-01
影响因子：
1.7
通讯作者：
Rashidi, MR
中科院分区：
文献类型：
--
作者：
Ghafourian, T;Rashidi, MR
醛氧化酶是一种含钼酶，分布于整个动物界。虽然这种酶是能够代谢范围广泛的醛类和N-杂环化合物，有没有详细的研究报告的酶-底物相互作用的物理化学要求。因此，本研究的目的是定量研究醛氧化酶催化氧化酞嗪和喹唑啉衍生物（作为底物）的动力学常数与其结构参数之间的关系。多元回归和逐步回归分析表明，酞嗪类化合物的极性（以偶极矩μ、内聚能密度δ（T）和R1取代基HBA的氢键受体能力为指标变量）对酶活性有负面影响（导致Vmax降低，Km升高）。喹唑啉系列中的吸电子取代基有利于与酶的相互作用。这一发现以及1/K-m.酞嗪类化合物的最低未占分子轨道能量和分子中两个氮原子的键合程度与酞嗪类化合物的log Vmax/IogK（m）的关系与其作用机理一致。该反应涉及对缺电子sp（2）-杂化碳原子的亲核攻击，并在破坏芳族结构后形成环氧化物中间体。
Aldehyde oxidase is a molybdenum-containing enzyme distributed throughout the animal kingdom. Although this enzyme is capable of metabolizing a wide range of aldehydes and N-heterocyclic compounds, there is no reported detailed study of physicochemical requirements of the enzyme-substrate interactions. The aim of this study, therefore, was to investigate quantitatively the relationships between the kinetic constants of aldehyde oxidase-catalyzed oxidation of some phthalazine and quinazoline derivatives (as substrates) and their structural parameters. Multiple regression and stepwise regression analyses showed that polarity of phthalazines (expressed as dipole moment mu cohesive energy density delta (T) and an indicator variable for hydrogen-bond acceptor ability of R1 substituent, HBA) had a negative effect on the enzyme activity (leading to the reduction of V-max and increase of K-m). Electron withdrawing substituents in the quinazoline series are favorable for interaction with the enzyme. This finding and also the relationships of 1/K-m. of phthalazines with the energy of the lowest unoccupied molecular orbital and log V-max/IogK(m) of phthalazines with degree of bonding of the two nitrogen atoms in the molecules are consistent with the mechanism of action. The reaction involves a nucleophilic attack on an electron-deficient sp(2)-hybridized carbon atom and formation of an epoxide intermediate following the disruption of the aromatic structure.