Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases

Mar Drugs. 2017 Oct 17;15(10):316. doi: 10.3390/md15100316.

Abstract

A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.

Keywords: 2-aminoimidazolone alkaloids; Alzheimer’s disease; CLK; Calcarea; DYRK; Down syndrome; Polyandrocarpa; Porifera; ascidian; kinase inhibitor; leucettamine B; leucettine; marine sponge; polyandrocarpamines; protein kinases.

Publication types

  • Review

MeSH terms

  • Alkaloids / chemical synthesis
  • Alkaloids / pharmacology*
  • Alkaloids / therapeutic use
  • Alzheimer Disease / drug therapy
  • Amines / chemical synthesis
  • Amines / pharmacology
  • Amines / therapeutic use
  • Animals
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / pharmacology
  • Antiprotozoal Agents / therapeutic use
  • Down Syndrome / drug therapy
  • Dyrk Kinases
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Phosphorylation
  • Phylogeny
  • Porifera / chemistry*
  • Porifera / genetics
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protozoan Infections / drug therapy
  • Protozoan Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • Urochordata / chemistry*

Substances

  • 2-aminoimidazolone
  • Alkaloids
  • Amines
  • Antiprotozoal Agents
  • Imidazoles
  • Protein Kinase Inhibitors
  • Protozoan Proteins
  • leucettamine B
  • polyandrocarpamine A
  • polyandrocarpamine B
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases