第十五届海洋药物学术年会暨2021国际海洋药物研讨会

13 / 2021-10-08 20:23:24

Epigenetic Manipulation to Trigger Production of Guaiane-Type Sesquiterpenes from a Marine-Derived Spiromastix sp. Fungus with Anti-neuroinflammatory Effects

Epigenetic modification, Marine fungus, Spiromastix sp., Guaiane-type sesquiterpenes, Anti-neuroinflammation

Epigenetic manipulation of a deep-sea sediment-derived Spiromastix sp. fungus using suberoylanilide hydroxamic acid (SAHA) induction resulted in the activation of a terpenerelated biosynthetic gene cluster, and nine new guaiane-type sesquiterpenes, spiromaterpenes A-I (1−9), were isolated. Their structures were determined using various spectroscopic techniques, in association with the modified Mosher’s method, computed electronic circular dichroism (ECD) spectra, and chemical conversion for configurational assignments. Compounds 4−6 exhibited significant effects against the NO production on lipopolysaccharide (LPS)-induced microglia cells BV-2, and the preliminary SAR analyses demonstrated that a 2(R),11-diol unit is favorable. The most active 5 abolished LPS-induced NF-κB translocation from the cytosol to the nucleus in BV-2 microglial cells, accompanied by the marked reduction of the transcription levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α dose-dependently in both LPS-induced BV-2 and BV-2 cells, as well as the protein and mRNA levels of iNOS and COX-2. Molecular docking approach demonstrated the inhibitory effect of 5 toward the iNOS protein related to the binding capability with its active pocket, and clarified the the configuration of C-2 in 5 playing a virtual role for iNOS inhibition. This study complements the gap in knowledge regarding the anti-neuroinflammatory activity of guaiane-type sesquiterpenoids at the cellular level and suggests that 5 is promising for further optimization as a multifunctional agent for anti-neuroinflammation.