Xia Wei

1. Mangrove ecosystems, situated at the dynamic interface between terrestrial and marine environments, are defined by extreme conditions such as high temperatures, elevated salinity, intense ultrav...

One pair of novel enantiomers, gigantdioxin A (+)-1 and B (−)-1, with a skeleton of benzo[d][1,3]dioxin; a new acetophenone gigantone A (3); a known 3-chlorogentisyl alcohol (2), which is the bioprecursor of 1; acetophenone (4); and chromone derivative (5) were obtained from the sponge-associated fungus Aspergillus giganteus MA46-5. Their structures were established by extensive and in-depth spectral analysis, such as UV, 1D and 2D NMR, and HRESIMS. The absolute configurations of (±)-1 were deduced by ORD, chiral separation, and experimental and computational ECD. Meanwhile, we proposed a possible biosynthetic pathway of (±)-1. Fortunately, the pathway was proved by biomimetic synthesis through 2, as a bioprecursor, reacted with n-butyraldehyde. Myocardial protection assays showed that 3 and 4 possessed stronger protective effects than a positive control against myocardial cell H9c2 ischemia–reperfusion injury in low concentrations, and the effect of (−)-1 was almost equal to that of the positive control. Further, we explored the possible mechanism of myocardial protection through network pharmacology. Adenosine A2a receptor (ADORA2A) and serum albumin (ALB) represent potential targets for myocardial protection associated with (−)-1 and 4, respectively. Based on the network pharmacology, we docked the predicted proteins with bioactive compounds using Autodock Vina.

Penicilloneines A (1) and B (2) are the first reported quinolone-citrinin hybrids. They were isolated from the starfish-derived fungus Penicillium sp. GGF16-1-2, and their structures were elucidated using spectroscopic, chemical, computational, and single-crystal X-ray diffraction methods. Penicilloneines A (1) and B (2) share a common 4-hydroxy-1-methyl-2(1H)-quinolone unit; however, they differ in terms of citrinin moieties, and these two units are linked via a methylene bridge. Penicilloneines A (1) and B (2) exhibited antifungal activities against Colletotrichum gloeosporioides, with lethal concentration 50 values of 0.02 and 1.51 mu g/mL, respectively. A mechanistic study revealed that 1 could inhibit cell growth and promote cell vacuolization and consequent disruption of the fungal cell walls via upregulating nutrient-related hydrolase genes, including putative hydrolase, acetylcholinesterase, glycosyl hydrolase, leucine aminopeptidase, lipase, and beta-galactosidase, and downregulating their synthase genes 3-carboxymuconate cyclase, pyruvate decarboxylase, phosphoketolase, and oxalate decarboxylase.

Two new disubstituted maleimides, aspergteroids G–H (1–2), and two trisubstituted butenolides aspergteroids I–J (3–4), along with four known analogs, were isolated and structurally identified from the fermentation extract of soft-coral-associated symbiotic and epiphytic fungus Aspergillus terreus EGF7-0-1. The structures of the new compounds were established mainly via spectroscopic data analyses, and their absolute configurations were determined via X-ray diffraction analysis and comparison of the calculated and experimental electronic circular dichroism. Myocardial protection assays showed that compounds 1, 2, 5, and 6 possess protective effects against tert-butyl hydroperoxide (TBHP)-induced H9c2 (rat myocardial cells) apoptosis at low concentrations. Based on the analyses of the protein–protein interaction (PPI) network and Western blotting, compound 1 may inhibit the apoptosis and inflammatory response of cardiomyocytes after TBHP induction and improve the antioxidant capacity of cardiomyocytes. We speculate that the anti-inflammatory response of compound 1 is suppressed by the glycogen synthase kinase-3 beta (GSK-3β), downregulated by the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation, and suppressed by the expression of cysteinyl aspartate specific proteinase-3 (caspase-3) and B-cell lymphoma-2 associated X protein (Bax).

Four novel, rare carbon-bridged citrinin dimers, namely dicitrinones G–J (1–4), and five known analogs (5–9) were isolated from the starfish-derived fungus Penicillium sp. GGF 16-1-2. Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculations. Compounds 1–9 exhibited strong antifungal activities against Colletotrichum gloeosporioides with LD₅₀ values from 0.61 μg/mL to 16.14 μg/mL. Meanwhile, all compounds were evaluated for their cytotoxic activities against human pancreatic cancer BXPC-3 and PANC-1 cell lines; as a result, compound 1 showed more significant cytotoxicities than the positive control against both cell lines. In addition, based on the analyses of the protein-protein interaction (PPI) network and Western blot, 1 could induce apoptosis by activating caspase 3 proteins (CASP3).

Four new benzodipyran racemates, namely (±)-aspergiletals A–D (3–6), representing a rare pyrano[4,3-h]chromene scaffold were isolated together with eurotiumide G (1) and eurotiumide F (2) from the soft-coral-derived fungus Aspergillus sp. EGF 15-0-3. All the corresponding optically pure enantiomers were successfully separated by a chiral HPLC column. The structures and configurations of all the compounds were elucidated based on the combination of NMR and HRESIMS data, chiral separation, single-crystal X-ray diffraction, quantum chemical ¹³C NMR, and electronic circular dichroism calculations. Meanwhile, the structure of eurotiumide G was also revised. The TDP1 inhibitor activities and photophysical properties of the obtained compounds were evaluated. In the TDP1 inhibition assay, as a result of synergy between (+)-6 and (−)-6, (±)-6 displayed strong inhibitory activity to TDP1 with IC₅₀ values of 6.50 ± 0.73 μM. All compounds had a large Stokes shift and could be utilized for elucidating the mode of bioactivities by fluorescence imaging.

Comprehensive analyses of the metabolite spectra of Aspergillus sp. EGF 15-0-3 under different culture conditions revealed the presence of unique environmental-induced metabolites exclusively from the rice medium. Subsequent target isolation afforded four unprecedented indole diketopiperazine-based hybrids with a pyrano[3′,2′:7,8]isochromeno[4,3-b]pyrazino[2,1-i]indole core (1 and 2) or a spiro[piperazine-2,2′-pyrano[3,4,5-de]chromene] scaffold (3 and 4). Putative biosynthetic pathways for 1–4, with Diels–Alder cycloadditions as key steps, were proposed. 1–4 exhibited selective cytotoxicities among several human cancer cells.