JBIC Journal of Biological Inorganic Chemistry

, Volume 15, Issue 7, pp 1157–1169 | Cite as

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

  • Paola Gramatica
  • Ester Papa
  • Mara Luini
  • Elena Monti
  • Marzia B. Gariboldi
  • Mauro Ravera
  • Elisabetta Gabano
  • Luca Gaviglio
  • Domenico Osella
Original Paper


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, 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.


Platinum complexes Anticancer drug Cytotoxicity Quantitative structure–activity relationship analysis 



Financial support for this work was from the Regione Piemonte (CIPE 2006 project-code A 370 and Ricerca Sanitaria Finalizzata 2009) and the ATF Association (Alessandria, Italy). The research was carried out within the framework of the European Cooperation COST D39 (Metallo-Drug Design and Action) and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB, Bari, Italy).

Supplementary material

775_2010_676_MOESM1_ESM.pdf (200 kb)
Supplementary material (PDF 200 kb)


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Copyright information

© SBIC 2010

Authors and Affiliations

  • Paola Gramatica
    • 1
  • Ester Papa
    • 1
  • Mara Luini
    • 1
  • Elena Monti
    • 2
  • Marzia B. Gariboldi
    • 2
  • Mauro Ravera
    • 3
  • Elisabetta Gabano
    • 3
  • Luca Gaviglio
    • 3
  • Domenico Osella
    • 3
  1. 1.QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Structural and Functional BiologyUniversità dell’InsubriaVareseItaly
  2. 2.Section of Pharmacology, Department of Structural and Functional BiologyUniversità dell’InsubriaBusto Arsizio (VA)Italy
  3. 3.Department of Environmental and Life SciencesUniversità del Piemonte Orientale “A. Avogadro”AlessandriaItaly

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