Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling.
Several Pt(IV) complexes of the general formula [Pt(L)2(L')2(L'')2] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands L'' 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, Ep, and partition coefficient, log Po/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 Po/w or the number of secondary sp3 carbon atoms) plus an electronic descriptor (Ep, 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.
QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Structural and Functional Biology, Università dell'Insubria, Via Dunant 3, 21100, Varese, Italy.
Paola
P
Gramatica
Ester
E
Papa
Mara
M
Luini
Elena
E
Monti
Marzia B
MB
Gariboldi
Mauro
M
Ravera
Elisabetta
E
Gabano
Luca
L
Gaviglio
Domenico
D
Osella
D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D021281:Quantitative Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000502:physiology
D009944:Organoplatinum Compounds