Metal-based paullones as putative CDK inhibitors for antitumor chemotherapy

J Med Chem. 2007 Dec 13;50(25):6343-55. doi: 10.1021/jm701042w. Epub 2007 Nov 13.

Abstract

Paullones constitute a class of potent cyclin-dependent kinase inhibitors. To overcome the insufficient solubility and bioavailability, which hamper their potential medical application, we aim at the development of metal-based derivatives. Two types of paullone ligands, L (1) - L (3) and L (4) , with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M (II)Cl(eta (6)- p-cymene)L]Cl ( 1- 4, L = L (1) - L (4) ; a, M = Ru; b, M = Os). The complexes were characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy and other physical methods. Complexes 1- 3, with a coordinated amidine unit, were found to undergo E/ Z isomerization in solution. The reaction was studied by NMR spectroscopy, and activation parameters Delta H (double dagger) and Delta S (double dagger) were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. (3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzazepines / chemical synthesis*
  • Benzazepines / chemistry
  • Binding Sites
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Drug Screening Assays, Antitumor
  • Guanosine Monophosphate / chemistry
  • Humans
  • Hydrolysis
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology
  • Osmium*
  • Rubidium*
  • Solutions
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzazepines
  • Indoles
  • Organometallic Compounds
  • Solutions
  • Osmium
  • Guanosine Monophosphate
  • Cyclin-Dependent Kinases
  • Rubidium