期刊
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
卷 15, 期 7, 页码 1157-1169出版社
SPRINGER
DOI: 10.1007/s00775-010-0676-4
关键词
Platinum complexes; Anticancer drug; Cytotoxicity; Quantitative structure-activity relationship analysis
资金
- Regione Piemonte [A 370]
- ATF Association (Alessandria, Italy)
Several Pt(IV) complexes of the general formula [Pt(L)(2)(L')(2)(LaEuro(3))(2)] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands LaEuro(3) are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, E (p), and partition coefficient, log P (o/w)) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log P (o/w) or the number of secondary sp (3) carbon atoms) plus an electronic descriptor (E (p), the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV) -> Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.
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