Synthesis and biological activity of pyrazole analogues of the staurosporine aglycon K252c

Bioorg Med Chem. 2016 Jul 15;24(14):3116-24. doi: 10.1016/j.bmc.2016.05.032. Epub 2016 May 18.

Abstract

A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1-3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity.

Keywords: Cytotoxicity; Molecular modeling; Pim kinase inhibition; Pyrazole; Staurosporine aglycon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-13 Magnetic Resonance Spectroscopy
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • K562 Cells
  • Models, Molecular
  • Protein Kinase C / drug effects
  • Protein Kinase C-alpha / drug effects
  • Proton Magnetic Resonance Spectroscopy
  • Pyrazoles / chemistry*
  • Spectrometry, Mass, Electrospray Ionization
  • Staurosporine / chemical synthesis*
  • Staurosporine / chemistry
  • Staurosporine / pharmacology*
  • Structure-Activity Relationship

Substances

  • Pyrazoles
  • protein kinase C gamma
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Staurosporine