Berkeleyones and Related Meroterpenes from a Deep Water Acid Mine Waste Fungus That Inhibit the Production of Interleukin 1-β from Induced Inflammasomes

Abstract

The Berkeley Pit, an acid mine waste lake, is a source of extremophilic microorganisms that produce interesting bioactive compounds. We have previously reported the isolation of berkeleydione 1, berkeleytrione 2, the berkeleyacetals and the berkeleyamides from the Pit Lake fungus Penicillium rubrum. In this paper we report the isolation and characterization of berkeleyones A-C (4, 5 and 7) as well as previously described preaustinoid A (3) and A1(6) from this same fungus. These compounds were evaluated as inhibitors of the signaling enzyme caspase-1 and as potential inhibitors of interleukin 1-β production by inflammasomes in induced THP-1 cell line assays.

3,5‐Dimethylorsellinic Acid Derived Meroterpenoids from Eupenicillium sp. 6A‐9, a Fungus Isolated from the Marine Sponge Plakortis simplex

“…The COSY and HMBC data associated with the D and E rings of 1 are present in the NMR spectra of 2 ( Figure 2), and the 1 H and 13 C NMR spectroscopic data of these two rings of 2 are comparable to those of 1 (Table 1), which provides ample evi- dence of the D and E rings and discloses the location of the last oxygen atom. Besides, much of the NMR spectroscopic data associated with the B ring and its isopropenyl and propionic acid side-chains of berkeleyone C (8) [10] are also present in the Figure 2). These data provide sufficient evidence for the ring B and its adjacently positioned isopropenyl and propionic acid substituent groups.…”

“…By comparing the spectroscopic and specific rotation data with literature values, the remaining four known compounds were identified as preaustinoid A1 (7), [9] berkeleyone C (8), [10] berkeleyacetal A (9), [11] and preaustinoid A3 (10) [12] (see Tables S9 and S10 in the Supporting Information), among which only the absolute configuration of preaustinoid A1 (7) was reported previously as shown. [19] In this work, we also clarified the absolute configurations of compounds 8-10.…”

“…In the evaluation of their cytotoxic activities, none of them displayed cytotoxicity toward the K562, A549, Jurkat, and HepG2 cell lines, even after treatment for 72 h at the highest dose of 20 μmol/ L. However, investigation of the immune-suppressive activities [32] of 1-4 and 6-10 showed dramatic inhibitory effects on tumor necrosis factor-α (TNF-α) secretion in lipopolysaccharide (LPS) induced THP-1 cells (Table 3). In previous studies, compounds 7 and 8 were also reported to show inhibition activity (IC 50 = 34.3 and 37.8 μM, respectively) against interleukin-1 production in induced THP-1 cells, [10] and compound 9 was reported to inhibit MMP-3 and caspase-1 in the millimolar range. [11] …”

“…zsq2 (FJ545752), isolated from the marine sponge Plakortis simplex, aroused our interest as its EtOAc extract had numerous derivatives showing MS peaks at m/z = 400-500 in the medium polarity area and had a plethora of split 1 H NMR peaks in the aromatic region (see Figures S1 and S2 in the Supporting Information). Next, large-scale fermentation and separation by preparative medium-pressure liquid chromatography (MPLC) and HPLC led to the isolation of the previously reported 22-deoxyminiolutelide B (6), [8] preaustinoid A1 (7), [9] berkeleyone C (8), [10] berkeleyacetal A (9), [11] and preaustinoid A3 (10) [12] as well as five new meroterpenoids, eupeniacetal A (1), eupeniacetal B (2), 1-methoxy-hydropreaustinoid A1 (3), hydroberkeleyone B (4), and 22-deoxy-10-oxominiolutelide B (5; Figure 1). The structures and absolute configurations of these compounds were illuminated by virtue of detailed spectroscopic analysis, single-crystal X-ray diffraction, and TDDFT/ECD and [α] D calculations on solution conformers.…”

Construction of Bridged Polycyclic Systems by Polyene Cyclization

“…An umber of meroterpenoids containing ab ridged [7.3.1.0 2,7 ] tricyclics ystem and their derivatives have been isolated and characterized as fungal metabolites since the discovery of neoaustin in 1994 ( Figure 1). [1,2] Although some of these natural products have been reported to display remarkable biological activities (e.g.,i nhibition of caspase-1), studies toward the synthesis of these meroterpenoids have not been reported to date.…”