α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian Synoicum prunum .

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D-I ( 4 - 9 ) and cis -prunolide C ( 10 ), a new dibrominated β-carboline sulfamate named pityriacitrin C ( 11 ), alongside the known prunolides A-C ( 1 - 3 ) were isolated from the Australian colonial ascidian Synoicum prunum . The prunolides D-G ( 4 - 7 ) represent the first asymmetrically brominated prunolides, while cis -prunolide C ( 10 ) is the first reported with a cis -configuration about the prunolide's bis-spiroketal core. The prunolides displayed binding activities with the Parkinson's disease-implicated amyloid protein α-synuclein in a mass spectrometry binding assay, while the prunolides ( 1 - 5 and 10 ) were found to significantly inhibit the aggregation (>89.0%) of α-synuclein in a ThT amyloid dye assay. The prunolides A-C ( 1 - 3 ) were also tested for inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model with prunolide B ( 2 ) displaying statistically significant inhibitory activity at 0.5 μM. The antiplasmodial and antibacterial activities of the isolates were also examined with prunolide C ( 3 ) displaying only weak activity against the 3D7 parasite strain of Plasmodium falciparum . Our findings reported herein suggest that the prunolides could provide a novel scaffold for the exploration of future therapeutics aimed at inhibiting amyloid protein aggregation and the treatment of numerous neurodegenerative diseases.