Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance

J Med Chem. 2015 Aug 27;58(16):6368-77. doi: 10.1021/jm501952r. Epub 2015 Aug 18.

Abstract

A series of platinum(II) complexes, characteristic of chiral trans-bicyclo[2.2.2]octane-7,8-diamine as ligand possessing dicyclic steric hindrance, were designed and synthesized. Biological evaluation showed that almost all complexes had cytotoxic activity against the tested cancer cell lines, among which most of chiral (R,R)-enantiomeres had stronger cytotoxicity than their (S,S)-counterparts, and 2a, [trans-bicyclo[2.2.2]octane-7R,8R-diamine](oxalato-O,O')platinum(II), is the most effective agent. Significantly, its counterpart, 2b, was much more sensitive to cisplatin resistant SGC7901/CDDP cancer cell line at a higher degree than 2a. Docking study and agarose gel electrophoresis revealed that the interaction of 2a with DNA was similar to that of oxaliplatin. Western blot analysis demonstrated that 2a could induce a better effect than cisplatin on a mitochondrial-dependent apoptosis pathway. Kinetic study indicated that the dicyclic ligand can accelerate the reaction rate of the complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • DNA, Neoplasm / drug effects
  • Diamines / chemical synthesis*
  • Diamines / metabolism
  • Diamines / pharmacology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Molecular Conformation
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / metabolism
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • Stereoisomerism

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Diamines
  • Ligands
  • Organoplatinum Compounds
  • Oxaliplatin