Maydistacins A-G, Terpestacin-type Sesterterpenoids with Anti-inflammatory Activity from the Phytopathogenic Fungus Bipolaris maydis.

Seven undescribed terpestacin-type sesterterpenoids, maydistacins A-G (1-7), along with two known congeners (8 and 9), were isolated from the phytopathogenic fungus Bipolaris maydis collected from the leaves of Hypericum longistylum. The structures of 1-7 were elucidated based on extensive spectroscopic analysis, chemical methods, NMR calculations with DP4+ probability analysis, and comparison of experimental and calculated electronic circular dichroism (ECD) calculations. In vitro anti-inflammatory effects of these compounds were tested in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Compound 1 exhibited inhibition of the production of nitric oxide in LPS-induced macrophages, with an IC50 value of 19 ± 2 µM. A dexamethasone control displayed an IC50 value of 6.7 ± 0.6 µM. Compound 1 is the first terpestacin-type sesterterpenoid reported to display anti-inflammatory activity and may provide a novel chemical scaffold for the discovery of new anti-inflammatory drugs.

Chaetoxylariones A-G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

K2S2O8-Mediated Radical Cyclization of 1,6-Enyne for the Synthesis of Diiodonated γ-Lactams.

A novel and convenient K2S2O8-mediated diiodo cyclization of 1,6-enynes for the facile synthesis of functionalized γ-lactam derivatives has been developed. This reaction features mild and transition-metal-free conditions, which offer a green and efficient entry to synthetically important γ-lactam scaffolds. Mechanistic studies suggest that iodide radicals initiate the cascade cyclic transformation.

Spectasterols, Aromatic Ergosterols with 6/6/6/5/5, 6/6/6/6, and 6/6/6/5 Ring Systems from Aspergillus spectabilis.

Spectasterols A-E (1-5), aromatic ergosterols with unique ring systems, were isolated from Aspergillus spectabilis. Compounds 1 and 2 possess a 6/6/6/5/5 ring system with an additional cyclopentene, while 3 and 4 have an uncommon 6/6/6/6 ring system generated by the D-ring expansion via 1,2-alkyl shifts. Compound 3 exhibited cytotoxic activity (IC50 6.9 µM) and induced cell cycle arrest and apoptosis in HL60 cells. Compound 3 was anti-inflammatory; it decreased COX-2 levels at the transcription and protein levels and inhibited the nuclear translocation of NF-κB p65.

A Removable Acyl Group Promoted the Intramolecular Dehydro-Diels-Alder Reaction of Styrene-Ynes: Highly Chemoselective Synthesis of Aryldihydronaphthalene Derivatives.

A removable acyl group promoted the intramolecular didehydro-Diels-Alder reaction of styrene-ynes under mild reaction conditions is proposed. The reaction is free of metals and catalysts, is easy to perform, and exhibits good functional group tolerance, providing a highly chemoselective approach for obtaining the valuable aryldihydronaphthalene derivatives.

A novel Gboxin analog induces OXPHOS inhibition and mitochondrial dysfunction-mediated apoptosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin's lymphoma. Currently, moderate efficacy and limitations of approved drugs still exist, and it is necessary to develop newer and more effective drugs. Gboxin is a promising inhibitor of OXPHOS, which specifically inhibits the growth of many kinds of cancer cell lines. In the present study, 21 Gboxin analogs incorporating amide and ester moieties were designed and synthesized. Preliminary screening results show that 5d also has specific selectivity for cancer cells, particularly on the DLBCL cells, which is weaker than that of Gboxin but still good. Thus, the effect and underlying mechanism of 5d on DLBCL cells were further studied. The results showed that 5d exhibits potent proliferation inhibition and cell cycle arrest effects, and its IC50 to DLBCL cells is below 1 µM. In addition, 5d induces apoptosis of DLBCL cells in a time- and dose-dependent manner, and this effect is stronger than that of Gboxin and VP16. Mechanistically, 5d plays its role mainly through the stimulation of metabolic stress in DLBCL cell lines, which induces OXPHOS inhibition, inflammation, DNA damage and mitochondrial dysfunction. These data suggest that 5d has potential as a candidate agent for DLBCL alternative drug development.

Bipolaquinones A-J, Immunosuppressive Meroterpenoids from a Soil-Derived Bipolaris zeicola.

Ten new meroterpenoids, bipolaquinones A-J (1-10), and one known congener, isocochlioquinone F (11), were isolated and identified from the fermented rice cultures of a soil-derived fungus, Bipolaris zeicola. The planar structures of 1-10 were elucidated based on extensive spectroscopic analyses (including HRESIMS and 1D and 2D NMR data), and their absolute configurations were determined by single-crystal X-ray diffraction analyses, comparison of experimental electronic circular dichroism (ECD) data, ECD calculations, and hydrolysis reaction. The immunosuppressive activity assay revealed that compounds 2, 3, and 7-10 showed significant inhibitory activity against concanavalin A (ConA)-induced T lymphocyte proliferation with IC50 values ranging from 4.1 to 9.4 µM, which furnished potential lead molecules for the design and development of new immunosuppressants for treating autoimmune-associated diseases.

Discovery of GOT1 Inhibitors from a Marine-Derived Aspergillus terreus That Act against Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating digestive system carcinoma with high incidence and death rates. PDAC cells are dependent on the Gln metabolism, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. Therefore, small molecule inhibitors targeting GOT1 can be used as a new strategy for developing cancer therapies. In this study, 18 butyrolactone derivatives (1-18) were isolated from a marine-derived Aspergillus terreus, and asperteretone B (5), aspulvinone H (AH, 6), and (+)-3',3'-di-(dimethylallyl)-butyrolactone II (12) were discovered to possess significant GOT1-inhibitory activities in vitro, with IC50 values of (19.16 ± 0.15), (5.91 ± 0.04), and (26.38 ± 0.1) µM, respectively. Significantly, the molecular mechanism of the crystal structure of GOT1-AH was elucidated, wherein AH and the cofactor pyrido-aldehyde 5-phosphate competitively bound to the active sites of GOT1. More importantly, although the crystal structure of GOT1 has been discovered, the complex structure of GOT1 and its inhibitors has never been obtained, and the crystal structure of GOT1-AH is the first reported complex structure of GOT1/inhibitor. Further in vitro biological study indicated that AH could suppress glutamine metabolism, making PDAC cells sensitive to oxidative stress and inhibiting cell proliferation. More significantly, AH exhibited potent in vivo antitumor activity in an SW1990-cell-induced xenograft model. These findings suggest that AH could be considered as a promising lead molecule for the development of anti-PDAC agents.

Fungal Polyketides with Three Distinctive Ring Skeletons from the Fungus Penicillium canescens Uncovered by OSMAC and Molecular Networking Strategies.

Four unusual polyketides possessing three unambiguous chemical architectures were discovered from the fermentation of Penicillium canescens assisted by the one strain-many compounds (OSMAC) strategy and MS2-based molecular networking. Penicanone (1) is the first naturally occurring polyketide characterized by a 6/6/8 tricyclic carbon skeleton incorporating an unusual bicyclo[5.3.1]hendecane core. Penicanesones A-C (2-4) are aromatic polyketide dimers simultaneously featuring inconsistent 6/5/5/6 and 6/6/5/6 heterotetracyclic ring cores. Their plausible biosynthetic pathways and screening of biological activity were described here.

Structurally diverse vibralactones produced by the fungus Stereum hirsutum.

Eight unexpected vibralactone homodimers, bisvibralactones A-H (1-8), and three new vibralactone monomers, hirsutumins A-C (9-11), were isolated from the culture of Stereum hirsutum. Their structures and absolute configurations were determined by detailed analyses of NMR, optical rotations, ECD, and high-resolution mass spectra as well as chemical transformation. Compounds 1-8 are unusual vibralactone dimers formed by the esterification of two vibralactone monomers. The absolute configurations of compounds 1 and 5 were determined by chemical conversions. All of the isolated compounds were evaluated for Porcine Pancreatic Lipase (PPL) inhibitory activities, and compound 10 showed significant inhibitory activity against PPL, with an IC50 value of 8.31 ± 1.04 µM.

New secondary metabolites with immunosuppressive activity from the phytopathogenic fungus Bipolaris maydis.

Three previously undescribed compounds, including a meroterpenoid, guignardone T (1), and two ophiobolin-type sesterterpenoids, maydispenoids A and B (2 and 3), along with four known compounds (4-7), were isolated from the phytopathogenic fungus Bipolaris maydis collected from Anoectochilus roxburghii (Wall.) Lindl leaves. The structures of all undescribed compounds were elucidated by spectroscopic analysis, electronic circular dichroism (ECD) calculations and single-crystal X-ray diffraction. Structurally, maydispenoids A was characterized by a fascinating decahydro-3-oxacycloocta[cd]pentalene fragment. It is notable that the compounds 2 and 3 exhibited potential inhibitory activity in anti-CD3/anti-CD28 monoclonal antibodies (mAbs) stimulated murine splenocytes proliferation, with IC50 values of 5.28 and 9.38 µM, respectively, and also suppress the murine splenocytes proliferation activated by lipopolysaccharide (LPS), with IC50 values of 7.25 and 16.82 µM, respectively. This is the first report of ophiobolin-type sesterterpenoids as immunosuppressor, and may provide new chemical templates for the development of new immunosuppressive drugs for autoimmune disease treatment.

α-Dicationic Chelating Phosphines: Synthesis and Application to the Hydroarylation of Dienes.

A series of new P^P-chelating ligands constituted by a dicationic -[P(H2Im)2]+2 unit (H2Im = 1,3-dimethyl-4,5-dihydroimidazol-2-ylidene) and a -PPh2 group connected through structurally different backbones have been synthesized. Evaluation of their reactivity toward different metal centers provides evidence that the dicationic fragment, otherwise reluctant to coordinate metals, readily participates in the formation of chelates when embedded into such a scaffold. Moreover, it significantly enhances the Lewis acidity of the metals to which it coordinates. This property has been used to develop a Rh catalyst that efficiently triggers the hydroarylation of dienes with electron-rich aromatic molecules. Kinetic studies and deuterium-labeling experiments, as well as density functional theory calculations, were performed in order to rationalize these findings.

α-Radical Phosphines: Synthesis, Structure, and Reactivity.

A series of phosphines featuring a persistent radical were synthesized in two steps by condensation of dialkyl-/diarylchlorophosphines with stable cyclic (alkyl)(amino)carbenes (cAACs) followed by one-electron reduction of the corresponding cationic intermediates. Structural, spectroscopic, and computational data indicate that the spin density in these phosphines is mainly localized on the original carbene carbon from the cAAC fragment; thus, it remains in the α-position with respect to the central phosphorus atom. The potential of these α-radical phosphines to serve as spin-labeled ligands is demonstrated through the preparation of several AuI derivatives, which were also structurally characterized by single-crystal X-ray diffraction.

Bis- and tris(pyrazolyl)borate/methane-stabilized P(III) -centered cations.

We report the synthesis of [H2 B(pz)2 PR](+) , [H2 C(pz)2 PR](+2) , [HB(pz)3 P](+2) , and [HC(pz)3 P](+3) (H2 B(pz)2 =bis(pyrazolyl)borate; H2 C(pz)2 =bis(pyrazolyl)methane; HB(pz)3 =tris(pyrazolyl)borate; HC(pz)3 =tris(pyrazolyl) methane; R=Ph, Cy or Et2 N) by reaction of the corresponding neutral or anionic ligands with chlorophosphines in the presence of TMSOTf. The structures of these compounds were determined by X-ray crystallographic analysis and the nature of their bonding was examined using density functional theory.

Discovery of bioactive polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons from Hypericum wilsonii.

In this work, nine previous undescribed polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons, cumilcinols A-I (1-9), along with six known analogues, were isolated and identified from the stems, leaves and flowers of Hypericum wilsonii. Their structures were determined by HRESIMS, NMR spectroscopic analysis, single-crystal X-ray crystallography as well as electronic circular dichroism calculations and comparisons. Compound 2 formed a unique furan ring bearing a rare acetal functionality. In bioassays, hyperacmosin G (13) could significantly inhibit the production of NO in LPS-stimulated RAW264.7 cell (IC50 = 4.350 ± 1.146 µM), and increased expression of related transcription factors at the gene level, inhibit the nuclear translocation of NF-κBp65, and reduce the protein expression of COX-2. Additionally, compound 5 showed significant inhibitory activity on Con A-induced T-lymphocyte proliferation (IC50 = 4.803 ± 3.149 µM), and treatment of 5 could reduce the increased ratio of CD4 and CD8 subpopulations induced by Con A in vitro. Those results indicated 13 possesses potential anti-inflammatory activity, and 5 exhibits a certain degree of immunosuppressive activity.

Polycationic ligands in gold catalysis: synthesis and applications of extremely π-acidic catalysts.

Very often ligands are anionic or neutral species. Cationic ones are rare, and, when used, the positively charged groups are normally appended to the periphery of the ligand. Here, we describe a dicationic phosphine with no spacer between the phosphorus atom and the two positively charged groups. This structural feature makes its donor ability poorer than that of phosphites and only comparable to extremely toxic or pyrophoric compounds such as PF3 or P(CF3)3. By exploiting these properties, a new Au catalyst has been developed displaying a dramatically enhanced capacity to activate π-systems. This has been used to synthesize very sterically hindered and naturally occurring 4,5-disubstituted phenanthrenes. The present approach is expected to be applicable to the development and improvement of many other transition metal catalyzed transformations that benefit from extremely strong π-acceptor ligands. The mechanism of selected catalytic transformations has been explored by density functional calculations.

A new diketopiperazine-type alkaloid from the endophytic fungus Penicillium expansum.

A chemical investigation on an endophytic fungus Penicillium expansum isolated from the medicinal plant Plantago depressa Willd. (Plantaginaceae) afforded one new diketopiperazine-type alkaloid, namely penicimine A (1), as well as two known congeners (2 and 3). Their structures were elucidated by widespread spectroscopic data, and the absolute configurations of 1 and 2 were further confirmed by single-crystal X-ray diffraction analyses. Compound 1 represented the first example of benzyl-containing diketopiperazine-type alkaloid bearing a methyl group attached at C-15 position. Compound 1 showed anti-inflammatory activity against LPS-induced nitric oxide (NO) production in RAW264.7 mouse macrophages with an IC50 value of 25.65 µM.

Collective synthesis of aspulvinone and its analogues by vinylogous aldol condensation of substituted tetronic acids with aldehydes.

A mild, modular and efficient synthetic method with broad substrate scope was developed for aspulvinones. Nine natural aspulvinones were synthesized, six of which were for the first time. The aldol condensation delivered Z-configuration products predominantly in MeCN. Meanwhile, alkoxy exchange occurred in MeOH and EtOH. Aspulvinone O and E, and substrate 49, 50, and 51 exhibited modest anti-SARS-CoV-2 activity in a high-throughput screening and enzyme kinetics assay.

ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism.

Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T-cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft-infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK-specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine-treated mice show a decrease in the number and activation of allograft-infiltrated T cells. It is further confirmed that lycorine-treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine-treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen-activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T-cell activation and allograft rejection.

Isolation, absolute configurations and bioactivities of pestaphilones A-I: Undescribed methylated side chain containing-azaphilones from Pestalotiopsis oxyanthi.

Nine undescribed side chain containing azaphilones, pestaphilones A-I, were isolated from the Anoectochilus roxburghii endophytic fungus Pestalotiopsis oxyanthi. The structures of these isolates were identified by spectroscopic data, electronic circular dichroism (ECD) calculations and comparisons, quantum-chemical 13C NMR calculations with DP4+ probability analysis, Rh2(OCOCF3)4-induced ECD, acetonide formation, selective oxidation reaction and X-ray crystallographic data. Structurally, pestaphilones A-I were the first azaphilones characteristically formed via a methyl group at C-9 in the C7 side chain. More importantly, a selective oxidation reaction was firstly set up to resolve the absolute configuration of flexible side chain containing azaphilones, and an acetonide formation based Rh2(OCOCF3)4-induced ECD experiment was performed to identify the configurations of the oxygenated pyranoquinone core in the azaphilones. In bioassay, pestaphilones A-F displayed potential immunosuppressive activity in concanavalin A (Con A)-induced T lymphocyte proliferation, with IC50 values ranging from (9.36 ± 1.14) µM to (35.21 ± 3.25) µM.