alpha-Synuclein Aggregation Inhibitory Procerolides and Diphenylalkanes from the Ascidian Polycarpa procera

The aggregation of the neuronal protein alpha-synuclein (alpha-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 alpha-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 alpha-syn aggregation inhibitory butenolide procerolide E (3) and one new alpha-syn aggregation inhibitory diphenylbutyrate methyl procerolate A (5). Herein we report the structure elucidation of procerolide E (3) and methylprocerolate A (5) and alpha-syn aggregation inhibitory activity of procerolides C-E (1-3), methyl procerolate A (5) and procerone A (4). We also report the alpha-syn binding activity of 3-bromo-4-methoxyphenylacetamide (6) and a synthetic butenolide library, which has allowed us to determine alpha-syn aggregation inhibitory structure-activity relationships for this class of compounds.