Cytotoxicity of cis-platinum(II) conjugate models. The effect of chelating arms and leaving groups on cytotoxicity: a quantitative structure-activity relationship approach

J Med Chem. 2005 Feb 10;48(3):857-66. doi: 10.1021/jm049508t.

Abstract

Thirteen newly synthesized or resynthesized diamine-platinum(II) complexes were characterized, and their cytotoxic activities (IC50) were tested on parental and resistant ovarian cancer cell lines. They represent models of conjugates between biologically active vectors and cytotoxic Pt(II) moieties within the "drug targeting and delivery strategy". Three drugs, routinely employed in the clinical treatment of cancer, namely, cisplatin, carboplatin, and oxaliplatin, were also included in the study as controls. The quantitative structure-activity relationship approach provides simple regression models able to predict log(1/IC50) of diamine-platinum(II) complexes on both parental and resistant ovarian cancer cell lines. The 16 complexes were characterized using 197 molecular descriptors, after which the best regression models relating a subset of these descriptors to the log(1/IC50) in the two cancer cell lines were calculated. Models with four variables proved to be endowed with very good predictive ability Q2(LMO-50%) > or = 85.6%, making it possible to discard 50% of the molecules from the test set following for cross-validation procedure. A four-variable regression model also proved effective in predicting the resistance index RI, Q2(LMO-50%) = 84.4%.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry*
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacology
  • Quantitative Structure-Activity Relationship
  • Regression Analysis
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Antineoplastic Agents
  • Chelating Agents
  • Organoplatinum Compounds
  • Cisplatin