A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs

J Med Chem. 2014 Aug 14;57(15):6751-64. doi: 10.1021/jm500791c. Epub 2014 Jul 30.

Abstract

A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry, Physical
  • Colonic Neoplasms / drug therapy
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Leukemia L1210 / drug therapy
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Mice, SCID
  • Models, Molecular
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacology
  • Oxidation-Reduction
  • Platinum*
  • Quantum Theory
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Organoplatinum Compounds
  • diaminocyclohexane)bis(malonato)platinum(IV)
  • Platinum