Antiproliferative Pt(IV) complexes: synthesis, biological activity and quantitative structure-activity relationship modeling

Several Pt(IV) complexes of the general formula
[Pt(L)2(L0)2(L00)2] [axial ligands L are Cl-, RCOO-, or
OH-; equatorial ligands L0 are two am(m)ine or one diamine;
and equatorial ligands L00 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.