Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase

Ghafourian, Taravat and Rashidi, Mohammad Reza (2002) Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase. Chemical and Pharmaceutical Bulletin, 49 (9). pp. 1066-1071. ISSN 0009-2363

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Abstract

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 μ, cohesive energy density δT 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 Vmax and increase of Km). Electron withdrawing substituents in the quinazoline series are favorable for interaction with the enzyme. This finding and also the relationships of 1/Km of phthalazines with the energy of the lowest unoccupied molecular orbital and log Vmax/logKm 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 sp2-hybridized carbon atom and formation of an epoxide intermediate following the disruption of the aromatic structure.

Item Type: Article
Keywords: aldehyde oxidase; heterocyclic compound; molybdenum; phthalazine derivative; quinazoline derivative, article; dipole; drug protein binding; drug structure; electron transport; energy; enzyme activity; enzyme kinetics; enzyme mechanism; enzyme substrate complex; hydrogen bond; liver; oxidation; protein metabolism; structure activity relation; structure analysis, Aldehyde Oxidoreductases; Algorithms; Enzyme Inhibitors; Humans; Kinetics; Liver; Oxidation-Reduction; Phthalazines; Quantitative Structure-Activity Relationship; Quinazolines
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Taravat Ghafourian
Date Deposited: 28 Nov 2017 13:34
Last Modified: 28 Nov 2017 13:34
URI: http://sro.sussex.ac.uk/id/eprint/64167

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