AS1041, a novel derivative of marine natural compound Aspergiolide A, induces senescence of leukemia cells via oxidative stress-induced DNA damage and BCR-ABL degradation.

Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of BCR-ABL tyrosine kinase. Imatinib was approved for CML therapy, however, BCR-ABL-dependent drug resistance, especially BCR-ABL-T315I mutation, restricts its clinical application. In this study, we reported anthraquinone lactone AS1041, a synthesized derivative of marine natural compound Aspergiolide A, showed anti-leukemia effect in vitro and in vivo by promoting cell senescence. Mechanistic study revealed the pro-senescence effect of AS1041 was dependent on oxidative stress-induced DNA damage, and the resultant activation of P53/P21 and P16INK4a/Rb. Also, AS1041 promoted ubiquitin proteasome system (UPS)-mediated BCR-ABL degradation, which also contributed to AS1041-induced senescence. In vivo, AS1041-induced senescence promoted tumor growth inhibition. In summary, the in vitro and in vivo antitumor effect of AS1041 suggests it can serve as a pro-senescence agent for alternative antileukemia therapy and imatinib-resistant cancer therapy by enhancing cellular oxidative stress and BCR-ABL degradation.

Nonenzymatic Self-Assembly Access to Diverse ortho-Quinone Methide-Based Pseudonatural Products.

A nonenzymatic self-assembly program was introduced to explore diverse clavatol-based pseudonatural products (PNPs) in a marine-derived fungus. Intermolecular couplings of the chemoreactive ortho-quinone methide of clavatol with native acceptors led to 14 clavatol-based PNPs with five categories, and compounds 1, 2, 5-10, and 12 are new. In particular, 1 and 2 possessed an unprecedented oxa-angular tetracyclic scaffold with highly oxidized modification and exhibited cytotoxicity. Such a program is proven to be of great advantage in constructing bioactive PNPs.

Linear polyketides produced by co-culture of Penicillium crustosum and Penicillium fellutanum.

Two new polyketides, penifellutins A (1) and B (2), possessing a 22 carbon linear skeleton, were isolated from a co-culture of the deep-sea-derived fungi Penicillium crustosum PRB-2 and Penicillium fellutanum HDN14-323. Meanwhile, two esterification products of 1, penifellutins C (3) and D (4), were obtained because compound 1 could be esterified spontaneously when stored in methanol. Their configurations were difficult to determine because of chiral central crowdedness, structural flexibility and instability. As such, we solved this issue by comprehensively using Mo2(OAc)4-based CD experiments, density functional theory calculation of 13C NMR, DP4 + probability analysis and many chemical reactions, including making acetonide derivative, Mosher's method, PGME method, etc. Compounds 1 and 2 show obvious inhibitory activity on the liver hyperplasia of zebrafish larvae at a concentration of 10 µmol/L, while 3 and 4 show no activity, indicating that two carboxyls in the structure are important active sites. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00125-8.

Pyrazinopyrimidine alkaloids from a mangrove-derived fungus Aspergillus versicolor HDN11-84.

Pyrazinopyrimidine-type alkaloids bearing a pyrazino[1,2-a] pyrimidine moiety, often have different functional groups substituted at C-8' or C-2'/C-8', generally further forming unique spiro-/conjugated ring systems. Four undescribed pyrazinopyrimidine-type alkaloids, including three natural products pyrasplorines A-C and an artifact deg-pyrasplorine B, as well as a biogenetically related versicoloid A were discovered from the extract of a mangrove-derived fungus Apergillus verisicolor HDN11-84. Pyrasplorine A contains unique spiral-type skeleton (composed of cyclopentenone ring with the pyrazino[1,2-a] pyrimidine core) which is unprecedented in pyrazinopyrimidine-type alkaloids. The deg-pyrasplorine B could be spontaneously converted from pyrasplorine B in mild conditions. Their structures including absolute configurations were elucidated based on NMR spectroscopic analysis, computational calculations and Marfey's method. The absolute configuration of versicoloid A was re-assigned in this study. All the isolated compounds are non-cytotoxic and deg-pyrasplorine B showed anti-influenza A virus H1N1 activity with the IC50 of 50 µM.

Polyhydroxy p-Terphenyls from a Mangrove Endophytic Fungus Aspergillus candidus LDJ-5.

Six undescribed polyhydroxy p-terphenyls, namely asperterphenyllins A-F, were isolated from an endophytic fungus Aspergillus candidus LDJ-5. Their structures were determined by NMR and MS data. Differing from the previously reported p-terphenyls, asperterphenyllin A represents the first p-terphenyl dimer connected by a C-C bond. Asperterphenyllin A displayed anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 53 µM and 21 µM, respectively. The anti-influenza virus A (H1N1) activity and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity of p-terphenyls are reported for the first time. Asperterphenyllin G exhibited cytotoxicity against nine cell lines with IC50 values ranging from 0.4 to 1.7 µM. Asperterphenyllin C showed antimicrobial activity against Proteus species with a MIC value of 19 µg/mL.

Ascandinines A-D, Indole Diterpenoids, from the Sponge-Derived Fungus Aspergillus candidus HDN15-152.

Four new indole diterpenoids, ascandinines A-D (1-4), were isolated from an Antarctic sponge-derived fungus Aspergillus candidus HDN15-152. Their structures, including absolute configurations, were established based on NMR data, computational calculations, and biosynthetic considerations. Ascandinine A (1) possesses an unprecedented 2-oxabicyclo[2.2.2]octan-3-ol motif embedded in a pentacyclic ring system, while compounds 2-4 represent a rare type of indole diterpenoid featuring the 6/5/5/6/6/6/6-fused ring system. Compound 3 displayed anti-influenza virus A (H1N1) activity with an IC50 value of 26 µM, while compound 4 showed cytotoxicity against HL-60 cells with an IC50 value of 7.8 µM.

Staprexanthones, Xanthone-Type Stimulators of Pancreatic ß-Cell Proliferation from a Mangrove Endophytic Fungus.

This project was focused on the discovery of novel compounds that promote endogenous ß-cell regeneration. Screening of extracts identified the fungus Stachybotrys chartarum as a promising candidate. After fermentation and extraction of S. chartarum, we isolated five new prenylated xanthones, namely, staprexanthones A-E (1-5), with staprexanthone A (1) being the first natural xanthone bearing a rare 4,5-dimethyl-1,3-dioxolane moiety. Compounds 1, 2, and 5 significantly increased ß-cell numbers in vivo in a zebrafish model. Further analysis revealed that 2 and 5 promoted ß-cell mass expansion by increasing proliferation of existing ß-cells though promotion of cell-cycle progression at the G1/S transition. These findings indicate that prenylated xanthones are potential new drug leads for antidiabetes therapy by stimulating ß-cell regeneration.

Fungal mycotoxin penisuloxazin A, a novel C-terminal Hsp90 inhibitor and characteristics of its analogues on Hsp90 function related to binding sites.

Hsp90 is a promising drug target for cancer therapy. However, toxicity and moderate effect are limitations of current inhibitors owing to broad protein degradation. The fungal mycotoxin penisuloxazin A (PNSA) belongs to a new epipolythiodiketopiperazines (ETPs) possessing a rare 3H-spiro[benzofuran-2,2'-piperazine] ring system. PNSA bound to cysteine residues C572/C598 of CT-Hsp90 with disulfide bonds and inhibits Hsp90 activity, resulting in apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. We identified that analogues PEN-A and HDN-1 bound to C572/C597 and C572 of CT-Hsp90α respectively, with binding pattern very similar to PNSA. These ETPs exhibited different effects on ATPase activity, dimerization formation and selectivity on client protein of Hsp90, indicating client recognition of Hsp90 can be exactly regulated by different sites of Hsp90. Our findings not only offer new chemotypes for anticancer drug development, but also help to better understand biological function of Hsp90 for exploring inhibitor with some client protein bias.

Dimeric Tetrahydroanthracene Regioisomers and Their Monomeric Precursor Produced by Streptomyces fumigatiscleroticus HDN10255.

Four new tetrahydroanthracene derivatives (1, 3-5) and a known antibiotic, A-39183A (2), were discovered from the marine-sponge-derived actinomycete Streptomyces fumigatiscleroticus HDN10255. Their structures including absolute configurations were elucidated based upon MS and NMR spectroscopic data, ECD calculations, and biogenetic considerations. Compounds 2 and 4 showed considerable cytotoxicity with the best IC50 value of 1.8 µM against HeLa cells.

Penispirozines A-H, Three Classes of Dioxopiperazine Alkaloids with Spirocyclic Skeletons Isolated from the Mangrove-Derived Penicillium janthinellum.

Eight new dioxopiperazine alkaloids, penispirozines A-H (1-8), were discovered from the mangrove-derived fungus Penicillium janthinellum HDN13-309. Their structures were elucidated by spectroscopic analysis, TDDFT-ECD calculations, and X-ray diffraction. Compound 1 had an unusual pyrazino[1,2]oxazadecaline coupled with a thiophane ring system, and compound 2 possessed a 6/5/6/5/6 pentacyclic ring system with two rare spirocyclic centers. Interestingly, compounds 3-8 were distinguished by not only the existence of a spiro-thiophane or spiro-furan ring system but also the chirality of the pentacyclic moiety. Compounds 3 and 4 increased the expression of the two relevant phase II detoxifying enzymes SOD2 and HO-1 at 10 µM.

Correction: Undecylprodigiosin Induced Apoptosis in P388 Cancer Cells Is Associated with Its Binding to Ribosome.

[This corrects the article DOI: 10.1371/journal.pone.0065381.].

Identification of Gliotoxin isolated from marine fungus as a new pyruvate kinase M2 inhibitor.

Pyruvate kinase M2 (PKM2) functions as an important rate-limiting enzyme of aerobic glycolysis that is involved in tumor initiation and progression. However, there are few studies on effective PKM2 inhibitors. Gliotoxin is a marine-derived fungal secondary metabolite with multiple biological activities, including immunosuppression, cytotoxicity, and et al. In this study, we found that Gliotoxin directly bound to PKM2 and inhibited its glycolytic activity in a dose-dependent manner accompanied by the decreases in glucose consumption and lactate production in the human glioma cell line U87. Moreover, Gliotoxin suppressed tyrosine kinase activity of PKM2, leading to a dramatic reduction in Stat3 phosphorylation in U87 cells. Furthermore, Gliotoxin suppressed cell viability in U87 cells, and cytotoxicity of Gliotoxin on U87 cells was obviously augmented under hypoxia condition compared to normal condition. Finally, Gliotoxin was demonstrated to induce cell apoptosis of U87 cells and synergize with temozolomide. Our findings identify Gliotoxin as a new PKM2 inhibitor with anti-tumor activity, which lays the foundation for the development of Gliotoxin as a promising anti-tumor drug in the future.

Chemoreactive-Inspired Discovery of Influenza A Virus Dual Inhibitor to Block Hemagglutinin-Mediated Adsorption and Membrane Fusion.

Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, we reveal the discovery of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated adsorption and membrane fusion using a chemoreactive ortho-quinone methide (o-QM) equivalent. Based on the o-QM equivalent nonenzymatically multipotent behavior, we created a series of clavatol-derived pseudo-natural products and found that penindolone (PND), a new diclavatol indole adduct, exhibited potent and broad-spectrum anti-IAV activities with low risk of inducing drug resistance. Distinct from current anti-IAV drugs, PND possesses a novel scaffold and is the first IAV inhibitor targeting both HA1 and HA2 subunits of virus hemagglutinin to dually block the IAV adsorption and membrane fusion process. More importantly, intranasal and oral administration of PND can protect mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. Thus, the use of chemoreactive intermediates could expand our understanding of chemical diversity and aid in the development of anti-IAV drugs with novel targets.

Irregularly Bridged Epipolythiodioxopiperazines and Related Analogues: Sources, Structures, and Biological Activities.

Epipolythiodioxopiperazines (ETPs) are a class of biologically active fungal secondary metabolites characterized by a bridged polysulfide piperazine ring. Regularly, the sulfide functionality is attached in the α-positions of the dioxopiperazine scaffold. However, ETPs possessing irregular sulfur bridges have rarely been explored. This review summarizes that 83 compounds of this subtype have been isolated and characterized since the discovery of gliovirin in 1982. Herein, particular emphasis is given to the isolation, chemistry, and biological activity of this subtype. For a better understanding, a relevant summary focusing on the source microorganisms and their taxonomy is provided and will help elucidate the fascinating chemistry and biology of these unusual ETPs.

Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes to cancer progression through multiple processes of cancer development, which makes it an attractive target for cancer therapy. The IL-6/STAT3 pathway is associated with an advanced stage in colorectal cancer patients. In this study, we identified trichothecin (TCN) as a novel STAT3 inhibitor. TCN was found to bind to the SH2 domain of STAT3 and inhibit STAT3 activation and dimerization, thereby blocking STAT3 nuclear translocation and transcriptional activity. TCN did not affect phosphorylation levels of STAT1. TCN significantly inhibited cell growth, arrested cell cycle at the G0/G1 phase, and induced apoptosis in HCT 116 cells. In addition, the capacities of colony formation, migration, and invasion of HCT 116 cells were impaired upon exposure to TCN with or without IL-6 stimulation. In addition, TCN treatment abolished the tube formation of HUVEC cells in vitro. Taken together, these results highlight that TCN inhibits various cancer-related features in colorectal cancer development in vitro by targeting STAT3, indicating that TCN is a promising STAT3 inhibitor that deserves further exploration in the future.

Amphiepicoccins A-J: Epipolythiodioxopiperazines from the Fish-Gill-Derived Fungus Epicoccum nigrum HDN17-88.

Ten new epipolythiodioxopiperazines (ETPs), namely, amphiepicoccins A-J (1-10), were isolated from the fish-gill-derived fungus Epicoccum nigrum HDN17-88. Their structures were deduced from extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Amphiepicoccin A (1) which contains an aromatic indole motif is unprecedented among the epicoccin type of ETPs. Compounds 1, 3, and 6 displayed anti-HSV-2 activities, with IC50 values of 70, 64, and 29 µM, respectively (acyclovir as positive control with an IC50 value of 31 µM), while 5 and 6 also revealed inhibitory activity against Bacillus subtilis with minimum inhibitory concentration (MIC) values of 13 and 25 µM, respectively.

Antibacterial Polyketides from Antarctica Sponge-Derived Fungus Penicillium sp. HDN151272.

Three new polyketides, ketidocillinones A-C (1-3), were discovered from the extract of an Antarctica sponge-derived fungus Penicillium sp. HDN151272. All the structures were deduced by spectroscopic data, including NMR and HRESIMS. The absolute configuration of compound 3 was established by using ECD calculation. Compounds 1-3 can be slowly oxidized to quinone form when exposed to air. Ketidocillinones B and C (2 and 3) exhibited potent antibacterial activity against Pseudomonas aeurigenosa, Mycobacterium phlei, and MRCNS (methicillin-resistant coagulase-negative staphylococci) with MIC values ranging from 1.56 to 25.00 µg/mL.

Prenylated p-Terphenyls from a Mangrove Endophytic Fungus, Aspergillus candidus LDJ-5.

Nine previously undescribed prenylated p-terphenyls, prenylterphenyllins F-J (1, 2, 4-6) and prenylcandidusins D-G (3, 7-9), were isolated from an endophytic fungus, Aspergillus candidus LDJ-5. Their structures were determined from NMR and MS data. Differing from previously reported p-terphenyls, compound 3 represents a rare 6,5,6,6-fused ring system. Compounds 4-6 are antimicrobial, and compounds 1, 4, 6, and 9 are cytotoxic.

Secondary Metabolites from Deep-Sea Derived Microorganisms.

Microorganisms obtained from the deep sea are a rich source of marine natural products with distinctive chemical structures and bioactivities. In this review, we will provide a retrospective of outstanding research within the scope of deep-sea (≥1000 m) microbial natural products, which has produced up to 442 compounds by the end of 2017. Approximetely, 60% of these structures have demonstrated various biological activities with more than 30% showing cytotoxic function. In this review, we particularly summarize those successful research on secondary metabolites produced by deep-sea derived microorganisms with inclusion of structural characteristics, biological activities, together with biogenetic origins and taxonomic features of the source microorganisms, from which, we expect to provide more comprehensive understanding of small molecules obtained from deep-sea environment and benefit the ongoing scholarly endeavors in the search for novel pharmaceutical agents from the deep-sea derived microorganisms.

New metabolites from a Mariana Trench-derived actinomycete Nocardiopsis sp. HDN 17-237.

One new ß,γ-butenoate derivative phenylbutenote (1), and one new α-pyrone nocapyrone T (2) were isolated from the deep-sea derived actinomycete Nocardiopsis sp. HDN 17-237. Their structures were elucidated by extensive HRMS, IR and NMR analyses. Among them, compound 1 is the first microbial natural products bearing a rare ß,γ-butenoate moiety, and compound 2 is the first α-pyrone isolated from strain of Mariana Trench. Compounds 1 and 2 were tested for antioxidant and antibacterial activities, while none of them showed significant activity.