Preparation and Biological Activity of 6-benzylaminopurine Derivatives in Plants and Human Cancer Cells

Bioorg Med Chem. 2006 Feb 1;14(3):875-84. doi: 10.1016/j.bmc.2005.09.004. Epub 2005 Oct 7.

Abstract

To study the structure-activity relationships of aromatic cytokinins, the cytokinin activity at both the receptor and cellular levels, as well as CDK inhibitory and anticancer properties of 38 6-benzylaminopurine (BAP) derivatives were compared in various in vitro assays. The compounds were prepared by the condensation of 6-chloropurine with corresponding substituted benzylamines. The majority of synthesised derivatives exhibited high activity in all three of the cytokinin bioassays employed (tobacco callus, wheat senescence and Amaranthus bioassay). The highest activities were obtained in the senescence bioassay. For some compounds tested, significant differences of activity were found in the bioassays used, indicating that diverse recognition systems may operate and suggesting that it may be possible to modulate particular cytokinin-dependent processes with specific compounds. Position-specific steric and hydrophobic effects of different phenyl ring substituents on the variation of biological activity were confirmed. In contrast to their high activity in bioassays, the BAP derivatives were recognised with much lower sensitivity than trans-zeatin in both Arabidopsis thaliana AHK3 and AHK4 receptor assays. The compounds were also investigated for their effects on cyclin-dependent kinase 2 (CDK2) and for antiproliferative properties on cancer and normal cell lines. Several of the tested compounds showed stronger inhibitory activity and cytotoxicity than BAP. There was also a significant positive correlation of the inhibitory effects on human and plant CDKs with cell proliferation of cancer and cytokinin-dependent tobacco cells, respectively. This suggests that at least a part of the antiproliferative effect of the new cytokinins was due to the inhibition of CDK activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzyl Compounds / chemical synthesis
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology
  • Biological Assay
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cytokinins / chemical synthesis
  • Cytokinins / chemistry
  • Cytokinins / pharmacology
  • Humans
  • Kinetin / chemical synthesis*
  • Kinetin / chemistry
  • Kinetin / pharmacology*
  • Mice
  • NIH 3T3 Cells
  • Plants / drug effects
  • Plants / metabolism
  • Purines / chemical synthesis
  • Purines / chemistry
  • Purines / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzyl Compounds
  • Cytokinins
  • Purines
  • Cyclin-Dependent Kinases
  • benzylaminopurine
  • Kinetin