Kinase Inhibitor Scaffolds against Neurodegenerative Diseases from a Southern Australian Ascidian, Didemnum sp.

Fabien Plisson, Melissa Conte, Zeinab Khalil, Xiao Cong Huang, Andrew M. Piggott, Robert J. Capon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase1 (CK1δ), cyclin-dependent kinase5 (CDK5) and glycogen synthase kinase3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarinsZ, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.

Original languageEnglish
Pages (from-to)983-990
Number of pages8
JournalChemMedChem
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 2012
Externally publishedYes

Keywords

  • Enzyme inhibitors
  • Kinases
  • Natural products
  • Neurodegenerative diseases
  • Ningalins

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