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Quantitatively analyzing the binding topology and reactivity is essential for understanding the cytotoxic or tumorigenic activities of bulky DNA adducts formed by chemotherapeutic drugs or carcinogens. Biochemical methods require purification of DNA and discontinuous steps to digest or label the adducts and thus have difficulties in identifying the binding topology and are not suitable for detecting unstable adducts. Herein, we used a single-molecule stretching assay to characterize the number of intercalative adducts, the formation kinetics, and the mechanical properties of intercalative DNA adducts based on measuring adduct-induced DNA elongation. We analyzed various reactive conditions, including formaldehyde-mediated anthracycline-DNA adducts, UV light-catalyzed psoralen-DNA adducts, and liver S9 fraction-catalyzed aflatoxin B

Asperflavipines C–E, three new cytochalasin heterotetramers, possessing a highly complex tetradecacyclic ring system with continuous bridged ring systems, and aspermichalasine A, possessing an unusual 5/6/5/8 ring system, were isolated.

Two novel alkaloids compounds together with fifteen know metabolites were identified from Aspergillus ochraceus. The stereochemistry features of the new molecules were determined via HRESIMS, NMR, ECD, and XRD analyses. Amongst these, compounds two compounds exhibited potential efficacy as anti‐Parkinson's disease with the EC50 values of 2.30 and 2.45 μm, respectively. ADMET prediction showed that these compounds owned favorable drug‐like characteristics and safe toxicity scores towards CNS drugs. Virtual screening analyses manifested that the compounds exhibited not only robust and reliable interactions to adenosine receptors A2A, but also higher binding selectivity to A2A receptors than to A1 and A3 receptors. Molecular dynamics simulation demonstrated the reliability of molecular docking results and the stability of the complexes obtained with the novel compounds and A2A receptors in natural environments. It is the first time that anti‐PD lead compounds have been identified from Aspergillus ochraceus and targeting adenosine A2A receptors., Prenylated indole alkaloid 14 exhibited the potential efficacy towards MPP+ insult SH‐SY5Y cells with the EC50 values of 2.30 μm. Virtual screening data manifested that 14 exhibited higher binding selectivity to A2AR than to A1R and A3R. Molecular dynamics simulation demonstrated the reliability of molecular docking results and the stability of 14‐A2AR complex in natural environments.

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 IC

Two undescribed

Hyperbeanone A (1), a novel 5,6-seco-polycyclic polyprenylated acylphloroglucinol (PPAP) derivative characterized by an undescribed benz[f]indene-1,9(4H)-dione ring system fused to a tricyclic γ-lactone unit via a ketone carbonyl, together with a known biosynthetic analogue (2), were isolated from the aerial parts of Hypericum beanii. The structure including absolute configuration of 1 was elucidated by extensive analysis of spectroscopic data (mainly including HRESIMS and 1D and 2D NMR) in combination with 13C NMR prediction, calculated 1H/13C NMR-DP4+ probability analyses, and electronic circular dichroism (ECD) methods. The key retro-Claisen, keto–enol, and [4 + 2] cyclization reactions were proposed for the biosynthetic assembly of new scaffold of 1. Compound 1 exhibited specific cytotoxicities against HL-60 (human acute myeloid leukemia) and SU-DHL-4 (diffuse large B-cell lymphoma) cell lines with IC50 values of 7.07 and 12.49 μM, respectively, with no obvious cytotoxicity to MEF (mouse embryonic fibroblast) cells. Compound 1 also induced G1-phase cell cycle arrest and apoptosis in HL-60 and SU-DHL-4 cell lines.

Two undescribed α-pyrone-containing polyketide derivatives designated aurovertins V (1) and W (2), and a known analogue (3), were isolated from the fungus Aspergillus aureoterreus. Their structures including the absolute configuration were elucidated on the basis of extensive spectroscopic methods and theoretical ECD calculation. Compound 1 is the first example of aurovertins with a 7R configuration, whereas 2 comprises a S configuration for C-6 and a Z geometry of the double bond Δ8. Both 1 and 2 showed no cytotoxicity against human cancer cell lines HL-60, SU-DHL-2 and U266) at the concentration of 20.0 μM.

One new spirocyclic lactone, terreinlactone C (1), and one new benzopyran derivative, 2,2-dimethyl-3-hydroxychroman-6-aldehyde (2), were discovered from the fungus Aspergillus terreus. The chemical structures of compounds 1 and 2 were elucidated by detailedly analyzing NMR and HRESIMS data. Compound 1 is the first natural product with a 1-oxaspiro[4.5]decan-2-one ring system and a possible biogenetic pathway is proposed. Two compounds were tested for their cytotoxic activities against five human cancer cell lines.[Formula: see text].

Four undescribed ergostane-type steroids, (22E,24R)-4α,5α-epoxyergosta-9α,14β-dihydroxy-7,22-diene-3,6-dione, (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione, 12α-hydroxyergosta-7,22,24(28)-triene-3-one, and 3β,12α-dihydroxyergosta-7,24(28)-diene, along with a known congener (22E,24R)-9α,14β-dihydroxyergosta-4,7,22-triene-3,6-dione, were isolated from the fungus Lasiodiplodia pseudotheobromae. Their structures were elucidated using NMR, HRESIMS, ECD calculation, and X-ray diffraction analyses. (22E,24R)-4α,5α-epoxyergosta-9α,14β-dihydroxy-7,22-diene-3,6-dione and (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione are a pair of C-14 epimers possessing an unusual epoxy group between C-4 and C-5, which was demonstrated using single-crystal X-ray diffraction analyses. The absolute configurations of 12α-hydroxyergosta-7,22,24(28)-triene-3-one and 3β,12α-dihydroxyergosta-7,24(28)-diene were determined by ECD calculations. Moreover, 3β,12α-dihydroxyergosta-7,24(28)-diene exhibited neuroprotective activity in vitro in glutamate-treated SH-SY5Y cell lines.

Kiiacylphnols A-H, eight previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs), along with two known congeners (hyperforcinol F and oxepahyperforin), were obtained from Hypericum przewalskii Maxim. The structures of these metabolites were confirmed by spectroscopic analyses, quantum-chemical

Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient of Anoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.

Ten sesterterpenoids, including eight undescribed ones named spectanoids A−H and two known analogs, were obtained from Aspergillus spectabilis. Their structures, including absolute configurations, were determined based on HRESIMS, NMR, ECD calculations and single-crystal X-ray diffraction analyses. Spectanoids A−G are tricyclic sesterterpenoids with an unusual 5/12/5 ring system, while spectanoid H possesses a 5/8/6/5 ring system. All of these compounds were evaluated for their cytotoxic activities against three human cancer cells, and spectanoid A, spectanoid C and spectanoid F exhibited moderate cytotoxic activities with IC50 values ranging from 12.1 to 26.1 μM.

Cytochalasans are a group of fungal-derived natural products characterized by a perhydro-isoindolone core fused with a macrocyclic ring, and they exhibit a high structural diversity and a broad spectrum of bioactivities. Cytochalasans have attracted significant attention from the chemical and pharmacological communities and have been reviewed previously from various perspectives in recent years. However, continued interest in the cytochalasans and the number of laboratory investigations on these compounds are both growing rapidly. This contribution provides a general overview of the isolation, structural determination, biological activities, biosynthesis, and total synthesis of cytochalasans. In total, 477 cytochalasans are covered, including "merocytochalasans" that arise by the dimerization or polymerization of one or more cytochalasan molecules with one or more other natural product units. This contribution provides a comprehensive treatment of the cytochalasans, and it is hoped that it may stimulate further work on these interesting natural products.

Two cysteine residue containing merocytochalasans (cyschalasins A and B, 1 and 2) and two 17,18-seco-aspochalasins (secochalasins A and B, 3 and 4) were isolated from the endophytic fungus Aspergillus micronesiensis. Cyschalasins A and B represent a new type of merocytochalasan featuring the fusion of an aspochalasin with a modified cysteine residue. Secochalasins A and B are the first 17,18-seco-aspochalasins to be reported and represent a previously undescribed carbon skeleton. Plausible biosynthetic pathways of 1-4 were proposed. Compounds 1 and 2 were cytotoxic and active against Gram-positive bacteria.

Chemical investigation of the plant endophytic fungus Pestalotiopsis sp. afforded two new butenolides, pestalolides B and C (1 and 2), two new diphenyl ethers, pestalotethers E and F (3 and 4), together with seven known compounds (5–11). Their structures were established by extensive spectroscopic analyses and the absolute configuration of 1 was further confirmed by ECD calculation. Structurally, compound 1 represents the first example of a new type of butenolide derivatives, bearing an unprecedented carbon scaffold having 13 carbon atoms. Compounds 1–4 were evaluated for the cytotoxic activities, and compound 1 showed remarkable inhibitory potency against human tumor HL60, U87MG, MDA-MB-231, and HEP-3B cell lines, with IC50 values of 1.42, 5.90, 5.90, and 4.29 μM, respectively.

Spirohypolactones A (1) and B (2) and hyperhexanones C–E (3–5), five degraded cyclohexanone-monocyclic polyprenylated acylphloroglucinol (C-MPAP) derivatives were isolated from the stems and leaves of Hypericum perforatum. The structures of these compounds were established by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of naturally occurring C-MPAPs possessing 2-oxaspiro[4.5]decane spirocyclic skeletons. Compound 5 featured an unusual dodecahydro-4H-oxocino[4,3-g]benzofuran ring system. Notably, compounds 3 and 4 induce apoptosis in the acute myeloid leukemia cell lines NB4 and HL-60 by the activation of caspase-3, and degradation of PARP. The proposed biosynthetic pathways and biological activities are also discussed.

Brasilanones A-F and asperterreusines A-C, undescribed brasilane sesquiterpenoids and dihydrobenzofuran derivatives, were isolated from the marine-derived fungus Aspergillus terreus [CFCC 81836]. Their structures with absolute configurations were elucidated on the basis of spectroscopic data, X-ray crystallographic analyses, and electronic circular dichroism (ECD) calculations. Brasilanones A-F are unusual brasilane sesquiterpenoids with an α,β-unsaturated ketone unit, interestingly, brasilanones B-D are stereo isomers. All of the isolates were evaluated for their inhibitory activities against NO production and cytotoxic activities against five human cancer cell lines (HL-60, SW-480, A-549, MCF-7, and SMMC-7721). Brasilanones A and E showed moderate inhibitory effect with NO inhibition rates of 47.7% (p < 0.001) and 37.3% (p < 0.001) at the concentration of 40 μM. Asperterreusines A showed cytotoxicity against HL-60 and SW-480 cell lines with IC50 values of 15.3 and 25.7 μM, respectively.

Cytochalasans are a group of fungal-derived natural products characterized by a perhydro-isoindolone core fused with a macrocyclic ring, and they exhibit a high structural diversity and a broad spectrum of bioactivities. Cytochalasans have attracted significant attention from the chemical and pharmacological communities and have been reviewed previously from various perspectives in recent years. However, continued interest in the cytochalasans and the number of laboratory investigations on these compounds are both growing rapidly. This contribution provides a general overview of the isolation, structural determination, biological activities, biosynthesis, and total synthesis of cytochalasans. In total, 477 cytochalasans are covered, including "merocytochalasans" that arise by the dimerization or polymerization of one or more cytochalasan molecules with one or more other natural product units. This contribution provides a comprehensive treatment of the cytochalasans, and it is hoped that it may stimulate further work on these interesting natural products.

Under OSMAC strategy, seven unreported multioxidized aromatic polyketides, penicanesins A‒G, were discovered from a soil-derived fungus Penicillium canescens along with seven known compounds. Their structures were assigned by extensive 1D and 2D NMR spectra in combination with HRESIMS and single crystal X-ray diffraction. Absolute stereochemistry of penicanesins A and D were elucidated by theoretical ECD calculation. (±)-Penicanesins A and B are two pairs of racemic aromatic polyketides with an unusual 6/6/6/6 heterotetracyclic ring core. In bioassay, (−)-penicanesin A shows potential cytotoxicity against human cancer cell lines HL-60 and SW480 with IC50 values at 13.8 ± 0.6 and 12.5 ± 0.9 μM, respectively, whereas the enantiomer (+)-penicanesin A is less active.

The study of

Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)–one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.

Hyperformitins A–I (1–9), nine undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) with double-bond migration, along with four new isomers hyperformitins J–M (10–13), were isolated from Hypericum perforatum. Their structures and absolute configurations were determined by spectroscopic analyses including HRESIMS, IR, UV, NMR, and ECD, as well as optical rotation (OR) calculations. The absolute configurations of previously reported analogues, garsubellins D and C as well as garcinielliptones L and M, were assigned for the first time by NMR spectra and specific rotations analyses assisting with OR calculations. Selected compounds were tested for their immunosuppressive activities against lipopolysaccharide (LPS)-induced B lymphocyte proliferation. Compounds 1, 3, 4, 5, 7, and 11 showed inhibition activities against the proliferation of B lymphocyte with IC50 values ranging from 4.1 to 9.7 μM. Furthermore, the neuroprotective activities of the isolates against corticosterone (CORT)-induced injury in PC12 cells were also tested, and compounds 1, 12, and 13 exhibited neuroprotective effects with cell viabilities of 68.0%, 71.3%, and 68.4%, respectively under the concentration of 10 μM.

The new polyprenylated acylphloroglucinol derivatives 1–15 and the known furohyperforin (16) were isolated from the stems and leaves of Hypericum perforatum. Their structures were determined by analyses of NMR and HRESIMS data. Their absolute configurations were elucidated by a combination of electronic circular dichroism (ECD) and Rh2(OCOCF3)4-induced ECD, as well as X-ray diffraction crystallography. The new hyperforatin F (9) contains a unique acetyl functionality at C-1 of the bicyclo[3.3.1]nonane core. Hyperforatins G (10) and H (11) are similarly the first examples of naturally occurring [3.3.1]-type polycyclic prenylated acylphloroglucinols possessing a carbonyl functionality at C-32. The compounds were tested for their acetylcholinesterase (AChE) inhibitory activities and cytotoxic activities against a panel of human tumor cell lines. Compounds 3, 5, 6, 8, and 9 exerted moderate inhibitory activities (IC50 3.98–9.13 μM) against AChE.

Asperflavipines A (1) and B (2), two structurally complex merocytochalasans, were isolated from Aspergillus flavipes. Asperflavipine A (1), which contains two cytochalasan moieties and two epicoccine moieties, is the first cytochalasan heterotetramer to be discovered. It is uniquely defined by 5/6/11/5/6/5/6/5/6/5/5/11/6/5 fused tetradecacyclic rings with three continuous bridged ring systems. Asperflavipine B (2) is a cytochalasan heterotrimer containing a cytochalasan and two epicoccine moieties with a 5/6/11/5/5/6/5/6/5 nonacyclic ring system. The hypothetical biosynthesis of 1 and 2 is proposed to involve Diels-Alder and [3+2] cycloaddition reactions as key steps and reveals unparalleled plasticity in the biosynthesis of merocytochalasans. The existence of 1 adds a new dimension to the diversity of the cytochalasan family. Compound 1 showed moderate cytotoxicity and induced apoptosis in Jurkat, NB4, and HL60 cells through the activation of caspase-3 and degradation of poly(ADP-ribose) polymerase (PARP).

Two cysteine residue containing merocytochalasans (cyschalasins A and B

Amichalasines A–C (1–3), which represent a new type of cytochalasan heterotrimers, were isolated from Aspergillus micronesiensis PG-1. Compounds 1 and 2 possess an undecacyclic 5/6/11/5/5/6/6/5/11/6/5 ring system, and 3 has an additional furan ring with a dodecacyclic 5/6/11/5/5/6/6/5/5/11/6/5 ring system. 1 and 2 exhibited potent cytotoxic activities through apoptosis induction mediated by caspase-3 activation and PARP degradation, and their IC50 values against HL60 cells were 1.71 and 3.74 μM, respectively.

Figure S1. 1H NMR Spectrum of Aspulvinone O in MeOH-d4. Figure S2. 13C NMR Spectrum of Aspulvinone O in MeOH-d4. Figure S3. Original Western blot images. (DOCX 1258 kb).

(±)-Peniorthoesters A and B (±1 and ±2), two pairs of unprecedented spiro-orthoester enantiomers with a 1,4,6-trioxaspiro[4. 5]decane-7-one unit, were obtained from Penicillium minioluteum. Their structures were determined by spectroscopic methods, X-ray diffraction analyses, and ECD calculations. (±)-Peniorthoesters A and B are the first examples of spiro-orthoester enantiomers, and they represent the first spiro-orthoesters originating from fungi. All compounds showed potential inhibitory activities comparable to dexamethasone against NO production with IC50 values ranging from 14.2 to 34.5 μM.

Dibrefeldins A and B (1 and 2), two unexpected brefeldin A (BFA) dimers, as well as brefeldin F (3), brefeldin G (4), and 14-hydroxy-BFA (5), three new BFA derivatives, together with three new naturally occurring BFA derivatives (6–8) and four known analogues (9–12), were isolated from the fungus Penicillium janthinellum. Dibrefeldins A and B (1 and 2) represent the first examples of BFA dimers formed by an esterification between two BFA monomer units. Brefeldin F (3) has an α,β-unsaturated γ-lactone ring, and this moiety was first discovered in naturally occurring BFA derivatives. The structures and relative/absolute configurations of these derivatives were elucidated by extensive spectroscopic methods, 13C NMR calculations, and single-crystal X-ray diffraction. Compounds 1, 2, 8, and 9 showed excellent cytotoxic activities against six cancer cell lines with IC50 values ranging from 0.01 to 4.45 μM.

Cytochathiazines A-C (1-3), which represent a new type of merocytochalasan, were isolated from coculture of Chaetomium globosum and Aspergillus flavipes. Compounds 1-3 are the first natural products featuring an unprecedented 2 H-1,4-thiazine functionality. Plausible biosynthetic pathways for 1-3 with a chaetoglobosin and a dipeptide as the main constitutional units were proposed. Compound 2 induced apoptosis in leukemia cells through the activation of caspase-3 and the degradation of poly ADP-ribose polymerase.

Two bioactive merocytochalasans, epicochalasines A (1) and B (2), a new class of cytochalasans bearing unexpected scaffolds consisting of fused aspochalasin and epicoccine dimer moieties, were isolated from the liquid culture broth of Aspergillus flavipes. Both 1 and 2 possess a hendecacyclic 5/6/11/5/6/5/6/5/6/6/5 ring system containing an adamantyl cage and as many as 19 stereogenic centers; however, the fusion patterns of 1 and 2 differ greatly, thus resulting in different carbon skeletons. The absolute configurations of 1 and 2 were determined by X-ray diffraction and calculated ECD, respectively. The biogenetic pathways of 1 and 2 are proposed to involve Diels-Alder and nucleophilic addition reactions. Both 1 and 2 induced significant G2/M-phase cell-cycle arrest. Furthermore, we found that merocytochalasans induce apoptosis in leukemia cells through the activation of caspase-3 and the degradation of PARP.

Asperchalasine A (1), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B-D (2-4), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction techniques. Compound 1, which possesses an unprecedented 13-oxatetracyclo[7.2.1.1(2,5).0(1,6)]tridec-8,12-dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1-4 were described starting from the co-isolated compounds 5 and 6. More importantly, 1 induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells.

Ampelopsis grossedentata, an indigenous plant in southern China, has been used for treating pharyngitis in traditional Chinese medicine for hundreds of years. In this study, we explored the anti-inflammatory activity of dihydromyricetin (1), its major bioactive component, and the underlying mechanism of this action. We demonstrated that 1 suppressed the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) as well as increased the level of the anti-inflammatory cytokine interleukin-10 (IL-10) in lipopolysaccharide (LPS)-treated mice. Moreover, 1 was found to markedly inhibit the production of nitric oxide (NO) and the levels of TNF-α, IL-1β, and IL-6, whereas it increased the level of IL-10 in LPS-induced RAW 264.7 macrophage cells. Compound 1 also reduced the protein expression of inducible nitric oxide synthase (iNOS), TNF-α, and cyclooxygenase-2 (COX-2) in macrophage cells. Furthermore, 1 suppressed the phosphorylation of NF-kappa B (NF-κB) and IκBα as well as the phosphorylation of p38 and JNK but not ERK1/2 in LPS-stimulated macrophages. Taken together, the present results suggest that 1 exerts its topical anti-inflammatory action through suppressing the activation of NF-κB and the phosphorylation of p38 and JNK. Thus, 1 may be a potentially useful therapeutic agent for inflammatory-related diseases.

Deltonin is a steroidal saponin which could suppress tumor growth through suppressing angiogenesis, but the mechanisms have not been directly elucidated yet. In the present study, we showed that deltonin inhibited the proliferation of primary cultured human umbilical vein endothelial cells (HUVECs) in vitro; notably, it could significantly inhibit HUVECs migration, invasion, and tube formation, which are indispensable progresses of angiogenesis. We further demonstrated that deltonin could inhibit VEGF–induced blood vessel formation in vivo. What is more, we found that deltonin blocked VEGF triggered phosphorylation of key intracellular angiogenic molecules, such as VEGFR2, Src family kinase, focal adhesion kinase (FAK), extracellular signal-related kinase (Erk1/2) and AKT kinase, accompanied with the increase of phosphorylated P38MAPK. Taken together, the present study demonstrates that deltonin inhibits angiogenesis through regulating VEGFR2 signaling pathway as well as AKT/MAPK signaling pathways in endothelial cells.

Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways.

Aspergilasines A–D (1–4), four merocytochalasans with new skeletons, were isolated from the liquid culture broth of Aspergillus flavipes QCS12. Aspergilasine A (1) possesses a uniquely caged pentacyclo[7.2.0.14,11.02,7.05,10]dodecane skeleton with an unexpected cyclobutane ring that formed by the fusion of two epicoccine moieties via two [3 + 2] cycloadditions. Aspergilasines B–D (2–4) are key biosynthetic intermediates of epicochalasine B that fit well with our previous biosynthetic proposal.

A rare depsipeptide, chaetomiamide A (1), together with two known diketopiperazines (2, 3) were isolated from the cultures of endophytic fungus Chaetomium sp., which was isolated from the root of Cymbidium goeringii. Compound 1 represents a rare skeleton with a 13-membered ring system. It structure was established on the basis of spectroscopic data interpretation. The configuration of 1 was determined by NOESY and Marfey's analysis. These isolates were evaluated for anticancer activity and 3 displayed more potent cytotoxicity than the positive control cisplatin associated with G2/M cell cycle arrest. In addition, 3 induced apoptosis via caspase-3 induction and PARP cleavage, concomitantly with the increase of Bax and decrease of Bcl-2.

Two new tetracyclic cytochalasans, flavichalasines A and B (1 and 2), three new pentacyclic cytochalasans, flavichalasines C–E (3–5), and eight new tricyclic cytochalasans, flavichalasines F–M (6–13), together with eight known analogues (14–21), were isolated from the solid culture of Aspergillus flavipes. Structures of these new compounds were elucidated on the basis of extensive spectroscopic analyses including 1D, 2D NMR and HRESIMS data. Their absolute configurations were determined by comparison of their experimental ECD with either computed ECD or experimental ECD spectrum of known compound. The structure and absolute configuration of 2 were further determined by X-ray crystallographic diffraction. Flavichalasine A (1) represents the first example of cytochalasan with a terminal double bond at the macrocyclic ring and flavichalasine E (5) is the only cytochalasan with an α-oriented oxygen-bridge in D ring. These new compounds were evaluated for their cytotoxic activities against seven human cancer cell lines, of which, 6 and 14 displayed moderate inhibitory activities against tested cell lines. In addition, compounds 6 and 14 induced apoptosis of HL60 cells by activation of caspase-3 and degradation of PARP.