Chemometric Evaluation of the Significance of Molecular Structural Descriptors on Binding of Acridinone Derivatives to DNA

Marcin      Koba; Tomasz      Baczek

doi:10.2174/157018010791526278

Abstract

The acridinones represented by imidazo- and triazoloacridinones are a group of potential antitumor agents. The most active derivative, the antitumor imidazoacridone C-1311 expected to be used as a topoisomerase II poison, has been recently selected for extended preclinical and clinical trials. In the current study, one of the chemometric techniques, namely factor analysis was performed to model the relationships between several molecular structural descriptors and the ability of the selected acridinone derivatives to the noncovalent binding to DNA. The noncovalent binding to DNA was measured and expressed as DNA-duplexes stabilization. Factor analysis led to extract four main factors with eigenvalues higher than 1 and the total variance explanation was on the level of 84.5% (by the first three principal component). Among the molecular structural descriptors studied, the most significant influence was recognized for lipophilicity parameters, quantum-chemical parameters and electron affinity specifying parameters. Importantly, distribution of individual compounds on the plane determined by two principal components produced patterns in good agreement with their ability to noncovalent binding to DNA as well as with their chemical structures. Finally, the proposed FA-based strategy enabled to classify the tested acridinone derivatives in view of their ability to noncovalent interaction with DNA.

Keywords: Acridinones, Noncovalent binding to DNA, Factor analysis (FA), Lipophilicity, Structural descriptors

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