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

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.