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

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Holland, Darren C
Prebble, Dale W
Er, Safak
Hayton, Joshua B
Robertson, Luke P
Avery, Vicky M
Domanskyi, Andrii
Kiefel, Milton J
Hooper, John NA
Carroll, Anthony R
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2022
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Abstract

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.

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Journal of Natural Products

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Natural products and bioactive compounds

Marine and estuarine ecology (incl. marine ichthyology)

Medicinal and biomolecular chemistry

Traditional, complementary and integrative medicine

Science & Technology

Life Sciences & Biomedicine

Plant Sciences

Chemistry, Medicinal

Pharmacology & Pharmacy

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Holland, DC; Prebble, DW; Er, S; Hayton, JB; Robertson, LP; Avery, VM; Domanskyi, A; Kiefel, MJ; Hooper, JNA; Carroll, AR, α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian Synoicum prunum, Journal of Natural Products, 2022

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