NF-κB inhibitors, unique γ-pyranolγ-lactams with sulfde and sulfoxide moieties from Hawaiian plant Lycopodiella cernua derived fungus Paraphaeosphaeria neglecta FT462

LC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identifcation of four unique mercaptolactated γ-pyranol–γ-lactams, paraphaeosphaerides E–H (1–4) together with one γ-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1–5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute confguration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, α-methoxy-α-(trifuoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4+NMR calculations. All the compounds were tested against STAT3, A2780 and A2780cisR cancer cell lines, E. coli JW2496, and NF-κB. Compounds 1 and 3 strongly inhibited NF-κB with IC50 values of 7.1 and 1.5μM, respectively.