Kinase inhibitor scaffolds against neurodegenerative diseases from a Southern Australian ascidian, Didemnum sp.

Abstract

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (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 lamellarins Z, 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.

• Authors: Fabien Plisson, Melissa Conte, Zeinab Khalil, Xiao-Cong Huang, Andrew M Piggott, Robert J Capon
• Journal: ChemMedChem (ChemMedChem) Vol. 7 Issue 6 Pg. 983-90 (Jun 2012) ISSN: 1860-7187 [Electronic] Germany
• PMID: 22532438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Carbazoles
• Catechols
• Coumarins
• Protein Kinase Inhibitors
• Pyrroles
• ningalin E
• ningalin F
• ningalin G
• Casein Kinase Idelta
• Cyclin-Dependent Kinase 5
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• Animals
• Australia
• Binding Sites
• Carbazoles (chemistry, therapeutic use, toxicity)
• Casein Kinase Idelta (antagonists & inhibitors, metabolism)
• Catechols (chemistry, therapeutic use, toxicity)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Computer Simulation
• Coumarins (chemistry, therapeutic use, toxicity)
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Magnetic Resonance Spectroscopy
• Molecular Conformation
• Neurodegenerative Diseases (drug therapy)
• Protein Kinase Inhibitors (chemistry, therapeutic use, toxicity)
• Protein Structure, Tertiary
• Pyrroles (chemistry, therapeutic use, toxicity)
• Urochordata (chemistry, metabolism)