Kinase inhibitor scaffolds against neurodegenerative diseases from a southern Australian Ascidian, Didemnum sp.

• Published in: ChemMedChem
• Main Authors: Plisson, Fabien, Conte, Melissa, Khalil, Zeinab, Huang, Xiao-Cong, Piggott, Andrew M., Capon, Robert J.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2012
• Subjects: Enzyme inhibitors; Kinases; Natural products; Neurodegenerative diseases; Ningalins; 3000 Pharmacology; Toxicology and Pharmaceutics; 1303 Biochemistry; 1313 Molecular Medicine; 1605 Organic Chemistry; 3002 Drug Discovery; 3004 Pharmacology; Antarctic; Antarc*
• Online Access: https://espace.library.uq.edu.au/view/UQ:276231

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1d), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK3 beta) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins BD as the major metabolites, together with six minor metabolites, the new ningalins EG 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.