Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3049-53. doi: 10.1016/s0960-894x(03)00644-9.

Abstract

Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cyclization
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Isoenzymes / chemical synthesis
  • Isoenzymes / pharmacology
  • Maleimides / chemical synthesis*
  • Maleimides / pharmacology
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C beta
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Indoles
  • Isoenzymes
  • Maleimides
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein Kinase C
  • Protein Kinase C beta
  • Glycogen Synthase Kinase 3
  • bisindolylmaleimide