Sycosterol A, an α-Synuclein Inhibitory Sterol from the Australian Ascidian Sycozoa cerebriformis

During a recent biodiscovery study to identify new α-synuclein (α-syn) aggregation inhibitors, we screened 29 Australian marine sponge and ascidian extracts in an MS binding assay. This resulted in an extract from the ascidian Sycozoa cerebriformis showing activity toward α-syn. The bioassay and MS guided isolation process led to the identification of one new polyoxygenated sterol sulfate, sycosterol A (1). The structure of this low-yielding steroid was elucidated from HRMS and NMR analysis. Sycosterol A displayed moderate antiaggregation activity with 46.2% (±1.8) inhibition when screened against α-syn at a 5:1 (sycosterol A:α-syn) molar ratio. The α-syn antiaggregation activity displayed by 1 and the recent discovery of similar sterols with α-syn antiaggregation activity and potent antiprion activity suggest this unique class may be useful antineurodegenerative compounds.