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

Abstract

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 αsyn aggregation inhibitory structure-activity relationships for this class of compounds.

α-Synuclein Aggregation Inhibitory and Antiplasmodial Activity of Constituents from the Australian Tree Eucalyptus cloeziana

“…The link between amyloid protein aggregation inhibition and antiplasmodial activity reported herein for 1 is particularly interesting since Biosca and co-workers reported functional amyloid-like aggregates in various life stages of Plasmodium parasites . Our previous research on natural product α-syn aggregation inhibitors has highlighted that compounds containing two or more 4-hydroxyphenyl groups show aggregation inhibition. , We have further found that the antiplasmodial activities of β-triketones are directly linked to the presence of a syncarpic acid group. The syncarpic acid may be present either as an acyclic moiety or embedded in a heterocycle.…”

“…8 Our previous research on natural product α-syn aggregation inhibitors has highlighted that compounds containing two or more 4-hydroxyphenyl groups show aggregation inhibition. 11,47 We have further found that the antiplasmodial activities of β-triketones are directly linked to the presence of a syncarpic acid group. The syncarpic acid may be present either as an acyclic moiety or embedded in a heterocycle.…”

A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds

“…Prunolides D and E significantly inhibit the aggregation (>89%) of α-synuclein in a ThT amyloid dye assay . A Queensland collection of the ascidian Polycarpa procera provides the new procerolide E ( 141 ), methyl procerolate A ( 142 ), and the new natural product 3-bromo-4-methoxyphenylacetamide ( 143 ), previously known as a synthetic compound . Procerolides C, D and procerone A are described in ref .…”