Synthesis and biological evaluation of N9-cis-cyclobutylpurine derivatives for use as cyclin-dependent kinase (CDK) inhibitors

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4399-4404. doi: 10.1016/j.bmcl.2017.08.018. Epub 2017 Aug 12.

Abstract

A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.

Keywords: CDK2; CDK5; Cancer; Cyclobutylpurine; Dinaciclib; Kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / chemical synthesis
  • Purines / chemistry
  • Purines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Purines
  • Cyclin-Dependent Kinases