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

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D-I (-) and -prunolide C (), a new dibrominated β-carboline sulfamate named pityriacitrin C (), alongside the known prunolides A-C (-) were isolated from the Australian colonial ascidian . The prunolides D-G (-) represent the first asymmetrically brominated prunolides, while -prunolide C () is the first reported with a -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 (- and ) were found to significantly inhibit the aggregation (>89.0%) of α-synuclein in a ThT amyloid dye assay. The prunolides A-C (-) were also tested for inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model with prunolide B () displaying statistically significant inhibitory activity at 0.5 μM. The antiplasmodial and antibacterial activities of the isolates were also examined with prunolide C () displaying only weak activity against the 3D7 parasite strain of . 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.