α‑Synuclein Aggregation Inhibitory Procerolides and Diphenylalkanes from the Ascidian Polycarpa procera

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2023-03, Vol.86 (3), p.533-540
• Main Authors: Prebble, Dale W., Holland, Darren C., Hayton, Joshua B., Ferretti, Francesca, Jennings, Laurence K., Everson, Jack, Xu, Mingming, Kiefel, Milton J., Mellick, George D., Carroll, Anthony R.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Humans; Parkinson Disease - metabolism; Urochordata - metabolism
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.2c01140

The aggregation of the neuronal protein α-synuclein (α-syn) is intrinsically linked to the development and progression of Parkinson’s disease (PD). Recently we screened the MeOH extracts from 283 marine invertebrates for α-syn binding activity using an affinity mass spectrometry (MS) binding assay and found that the extract of the ascidian Polycarpa procera displayed activity. A subsequent bioassay-guided purification led to the isolation of one new α-syn aggregation inhibitory butenolide procerolide E (3) and one new α-syn aggregation inhibitory diphenylbutyrate methyl procerolate A (5). Herein we report the structure elucidation of procerolide E (3) and methylprocerolate A (5) and α-syn aggregation inhibitory activity of procerolides C-E (1–3), methyl procerolate A (5) and procerone A (4). We also report the α-syn binding activity of 3-bromo-4-methoxyphenylacetamide (6) and a synthetic butenolide library, which has allowed us to determine α-syn aggregation inhibitory structure-activity relationships for this class of compounds.