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Two new alkaloids, leptocarpinine B (1) and corydamine acid (2), with thirteen known alkaloid compounds (3–15), were isolated from Hypecoum leptocarpum. The structures of the isolated compounds were determined based on spectroscopic data analyses, including IR, ESI-MS, 1 D, and 2 D NMR. In addition, all the isolates were evaluated for cytotoxic activities. Compound 6 showed moderate cytotoxicity against human ovarian cancer cell lines (A2780), human cervical cancer cell lines (HeLa), and human hepatocellular carcinomas cell lines (HepG2).

One new phenolic derivative, 1-(4',5'-dihydroxy-2'-methylphenyl)-pentane-1,4-dione (1), along with eighteen known compounds including eight sesquiterpenoids (2–9), one triterpenoid (10), one bisdpoxylignan (11), one coumarin (12), and seven flavonoids (13–19) were isolated from the dried inflorescence of Tibetan herbal medicine Pulicaria insignis. The structure of 1 was established by spectroscopic methods, including HRESIMS, IR, 1D, and 2D NMR. All isolates were assessed for the cytotoxic activities against MGC-803, T24, HepG2, and HeLa cell lines using the MTT assay. The results showed that compound 1 displayed moderate cytotoxicity against Hela and HepG2, and compounds 3, 4, 5, 6, and 13 exhibited potential cytotoxic activities against the four cell lines with IC50 values ranging from 3.05 to 14.37 μM. Notably, compound 5 exhibited significant anti-proliferative activities against HepG2 cell lines with the IC50 values of 3.05 ± 0.36 μM. Further bioactivity investigation showed that compound 5 could block HepG2 cells in the G1 phase of the cell cycle, thereby inhibiting the growth of HepG2 cells and inducing apoptosis in HepG2 cells.

Hyperuricemia is a common metabolic disease and is one of the factors that could induce chronic kidney disease (CKD). Geniposide (GEN) is a typical natural iridoid glucoside compound with a series of biological activities, but the poor bioavailability of GEN limits its clinical application. In this context, the pharmacological activity of the geniposide-phospholipid complex (GEN-PLC) in ameliorating posthyperuricemia CKD was evaluated by in vitro and in vivo experiments in this study. In vitro cell experiments showed that GEN-PLC treatment markedly decreased inflammatory cytokine levels and reactive oxygen species levels compared with those of GEN in uric acid-treated HKC cells. In vivo research results confirmed that a high concentration of uric acid could cause CKD by increasing inflammatory cytokines and reactive oxygen species in hyperuricemic mice. At the same time, GEN-PLC could regulate the PI3K/AKT/NF-κB and Keap1/Nrf2/HO-1 signaling pathways to effectively inhibit the inflammatory response and oxidative stress, thereby ameliorating posthyperuricemia CKD, and the therapeutic effect was better than that of GEN. In addition, the preparation technology of GEN-PLC was optimized, and the physiochemical analysis explained the intermolecular interactions of the two components. Based on the research results, GEN-PLC could enhance the bioavailability of GEN and become a promising candidate for clinical drug development.

Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

Retinoic acid receptor related orphan receptor γt (RORγt), identified as the essential functional regulator of IL-17 producing Th17 cells, is an attractive drug target for treating autoimmune diseases. Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile. Efforts in reducing the lipophilicity and improving the LLE values led to the discovery of c9, which demonstrated potent RORγt inverse agonistic activity and consistent metabolic stability. During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases.

The predominant feature of type 2 diabetes is insulin resistance. Identifying a drug able to reduce insulin resistance is an urgent requirement. ent-3α-Formylabieta-8(14),13(15)-dien-16,12β-olide had been identified as a new diterpene derivative which showed anticancer activity. This study explores the hypoglycemic effect of ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide and studied its mechanism. The insulin response of HepG2 cells following ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide treatment, as a model for liver cancer cells, was assessed. The results demonstrated that hyperglycemia resulted in a significant increase in the levels of insulin receptor substrate-1 (IRS-1) serine phosphorylation and decrease in Akt phosphorylation. High glucose also inhibited the phosphorylation of insulin-dependent GSK3β. ent-3α-Formylabieta-8(14),13(15)-dien-16,12β-olide treatment improved the effect of insulin on the phosphorylation of IRS-1 Ser307. In addition, this study demonstrated that the effect of ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide was dependent on the activation of AMP-activated protein kinase. Collectively, experimental data indicated an association between insulin resistance and hyperglycemia in HepG2 cells, and that ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide reduces IRS-1 Ser307 phosphorylation via activating AMPK, thereby decreasing the insulin signaling blockade.

A new labdane-type diterpenoid, ent-19-ol-13-epi-manoyl oxide,19-undecane ester, together with ten known diterpenes, were isolated from the ethanolic crude extract of the fresh tubers of Sagittaria trifolia L. The chemical structures of these compounds were determined by extensive 2-D NMR experiments and by comparison with the data reported in the literature. These compounds showed different inhibitory effects on various human cancer cells. Among these, compound 11 exhibited potential inhibition effects against human colon cancer cells. Moreover, flow cytometry demonstrated that compound 11 arrested the cell cycle at the G1 phase and induced cellular apoptosis, accompanied by mitochondrial membrane potential reduction. Mechanistic studies revealed that treatment with compound 11 inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Compound 11 also inhibited the expression of c-Myc, Cyclin D1, and Bcl-2, the downstream targets of NF-κB. Therefore, our findings provided insight into the anticancer components of Sagittaria trifolia L. tubers, which could facilitate their utilization as functional food ingredients.

The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.

Gatekeeper T790M mutation in EGFR is the most common factor for acquired resistance. Acrylamide-bearing 4-anilinoquinazoline scaffold are powerful irreversible inhibitors for overcoming resistance. In this work, three series of EGFR inhibitors derived from incorporation of cinnamamide into the quinazoline scaffold were designed and synthesized to reverse resistance resulting from insurgence of T790M mutation. SAR studies revealed that methoxy and acetoxy substitutions on the cinnamic phenyl ring were found to elevate the activity. In particular, compound 7g emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib (0.95 μM) towards H1975 cells with an IC50 value of 1.22 μM. Kinase inhibition studies indicated that 7g showed excellent inhibitory effect on EGFRT790M enzyme, which was 11 times more effective than gefitinib. Besides, selectivity index of 7g toward the EGFRT790M mutant over the EGFRWT is 2.72, hinting its effect of reducing off-target. Mechanism study indicated that 7g induced apoptosis of H1975 cells and arrest the cell cycle at G2/M phase in a dose-dependent manner. Moreover, 7g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 7g inside EGFRWT and EGFRT790M binding sites.

Two new alkaloids, leptocarpinine B (

Four new purified polysaccharides (PAP) were isolated and purified from the Enteromorpha prolifera by alkali extraction, and further characterization was investigated. Their average molecular weights of PAP-1, PAP-2, PAP-3, and PAP-4 were estimated as 3.44 &times, 104, 6.42 &times, 104, 1.20 &times, 105, and 4.82 &times, 104 Da, respectively. The results from monosaccharide analysis indicated that PAP-1, PAP-2, PAP-3 were acidic polysaccharides and PAP-4 was a neutral polysaccharide. PAP-1 and PAP-2 mainly consist of galacturonic acid, while PAP-3 and PAP-4 mainly contained rhamnose. Congo red test showed that no triple helical structure was detected in the four polysaccharides. The antioxidant activities were investigated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), Superoxide, and 2, 2&prime, azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical assay. In vitro antitumor activities were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. PAP-1 exhibited relatively stronger antioxidant activities among the four polysaccharides in a dose-dependent manner. At a concentration of 1.00 mg/mL, the antioxidant activities of PAP-1 on the DPPH radical scavenging rate, superoxide anion radical scavenging rate, and ABTS radical rate at 1.00 mg/mL were 56.40%, 54.27%, and 42.07%, respectively. They also showed no significant inhibitory activity against MGC-803, HepG2, T24, and Bel-7402 cells. These investigations of polysaccharides provide a scientific basis for the use of E. prolifera as an ingredient in functional foods and medicines.

A new labdane-type diterpenoid, ent-19-ol-13-epi-manoyl oxide,19-undecane ester, together with ten known diterpenes, were isolated from the ethanolic crude extract of the fresh tubers of Sagittaria trifolia L. The chemical structures of these compounds were determined by extensive 2-D NMR experiments and by comparison with the data reported in the literature. These compounds showed different inhibitory effects on various human cancer cells. Among these, compound 11 exhibited potential inhibition effects against human colon cancer cells. Moreover, flow cytometry demonstrated that compound 11 arrested the cell cycle at the G1 phase and induced cellular apoptosis, accompanied by mitochondrial membrane potential reduction. Mechanistic studies revealed that treatment with compound 11 inhibited IKKα/β phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. Compound 11 also inhibited the expression of c-Myc, Cyclin D1, and Bcl-2, the downstream targets of NF-κB. Therefore, our findings provided insight into the anticancer components of Sagittaria trifolia L. tubers, which could facilitate their utilization as functional food ingredients.

A series of asiatic acid (AA) based 1,2,3-triazole derivatives were designed, synthesized and subjected to a cell-based NF-κB inhibition screening assay. Among the tested compounds, compound 6k displayed impressive NF-κB inhibitory activity with an IC(50) value in the low micromolar range. A molecular docking study was performed to reveal key interactions between 6k and NF-κB in which the 1,2,3-triazole moiety and the hydroxyl groups of the AA skeleton were important for improving the inhibitory activity. Subsequently, surface plasmon resonance analysis validated the high affinity between compound 6k and NF-κB protein with an equilibrium dissociation constant (KD) value of 0.36 μM. Further studies showed that compound 6k observably inhibited the NF-κB DNA binding, nuclear translocation and IκBα phosphorylation. Moreover, in vitro antitumor activity screening showed that compound 6k (IC(50) = 2.67 ± 0.06 μM) exhibited the best anticancer activity against A549 cells, at least partly, by inhibition of the activity of NF-κB. Additionally, the treatment of A549 cells with compound 6k resulted in apoptosis induction potency and in vitro cell migration inhibition. Thus, we conclude that AA based 1,2,3-triazole derivatives may be potential NF-κB inhibitors with the ability to induce apoptosis and suppress cell migration.

A phytochemical study of the EtOAc extract of Ligularia rumicifolia (J.R.Drumm.) S.W.Liu led to the isolation of two new monoterpene lactones (1-2) named (2S,3S,5R)-5-ethyl-2,3-dimethyl-6-oxoterahydro-2H-pyran-2-carboxylic acid and (2S,3S,5R)-5-ethyl-2,3-dimethyl-6-oxoterahydro-2H-pyran-2-carboxylic acid methyl ester, along with nine known compounds (3-11). All compounds were isolated from this species for the first time. Their structures were established on the basis of spectroscopic methods. The cytotoxic activity of Compound 2 was weak, with the lowest IC50 value of 80.84 μM against MCF-7 cells. Compound 1 exhibited better anti-proliferative activities against MCF-7, T-24, HepG-2 and SKOV-3 cell lines than Compound 2, with the lowest IC50 value of 66.12 μM against MCF-7 cells.

Potentilla discolor has been used as the Traditional Chinese Medicine ingredient in prescription for over 400 years, and scientific evidences have confirmed its effectiveness as an anticancer agent. The present study is undertaken to assess, for the first time, the chemical composition, potential in vitro anti-tumor activities and related mechanisms of the essential oil, which was extracted from Potentilla discolor fresh roots by supercritical CO2 fluid extraction technology. Twenty-nine compositions were identified by gas chromatography-mass spectrometry. The anti-tumor activity of the essential oil was screened against four cancer cell lines and the lowest IC50 value was 19.02 μg/mL on T24 cell line. Then, T24 was selected as a representative cell line for the related mechanism research. As a result, cell cycle assay confirmed that the cell growth was inhibited by Potentilla discolor essential oil and cell cycle was arrested in DNA synthesis phase. A series of apoptosis analysis indicated that Potentilla discolor essential oil induced apoptosis through mitochondrion-mediated intrinsic pathway. This study revealed that Potentilla discolor essential oil has significant anti-tumor activity. It should be useful in the search for new potential anti-tumor agents and pharmaceutical industries.

Six novel of Pt(IV) complexes comprising chalcone analogues were synthesized and evaluated for anti-proliferative activity using MTT assay. In vitro evaluation revealed that all Pt(IV) complexes showed better and more potent activity against three human cancer cells including CDDP resistant cells than that of their corresponding mother Pt(II) species. Among them, two representative complexes, 14 and 17, exhibited better cell selectivity between cancer cells and normal cells than CDDP. Molecular docking study indicated that complexes 14 and 17 could bind to the colchicine site of tubulin. Moreover, complexes 14 and 17 also remarkably displayed inhibition of cell migration against HUVEC cells in vitro. Molecular mechanism studies suggested that 14 and 17 induced production of reactive oxygen species (ROS), cell cycle arrest at the G2/M phase, and mitochondria-mediated apoptosis by regulating the expression of Bcl-2 family members.

An efficient strategy of using molecularly imprinted solid-phase extraction and high-speed counter-current chromatography (HSCCC) were established for separation and purification of three analogues from Clematis akebioides for the first time. The three analogues, including 26.30 mg caffeic acid, 84.20 mg p-coumaric acid, and 44.40 mg ferulic acid, were obtained from 200.00 mg of the crude sample. The molecularly imprinted polymer was prepared with caffeic acid as template molecule and acrylamide as functional monomers. The results showed that the caffeic acid and its analogues could be well enriched. Then, the extract was purified by HSCCC using a two-phase solvent system consisting of chloroform/acetonitrile/water/acetic acid (10:5:4:0.0004, v/v) and a continuous sample introduction system was adopted. The three organic acids were identified by 1H-NMR and 13C-NMR.

Series of novel alizarin and phosphoryl amino acid scaffold (4a–4d, 8a–8d) were synthesized and evaluated for the suppression of cancer cell proliferation in vitro against MGC-803, HepG2, T24, NCI-H460, and SK-OV-3 cell lines by standard 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay compared with commercial anticancer drug doxorubicin. Interestingly, all newly synthesized compounds exhibited relatively high cytotoxicity compared with alizarin and low cytotoxicity against human normal liver cell line HL-7702 cells. Especially, compound 8d showed the best cytotoxicity against SK-OV-3 cells with IC50 7.09 µM, which was slightly worse than that of drug doxorubicin. The cell apoptosis-inducing activity of representative compound 8d in SK-OV-3 cells revealed that the anticancer activity of this compound depended on apoptosis of cancer cells via regulation of Bcl-2 family members, activation of caspase-9 and caspase-3. Cell cycle analysis confirmed that compound 8d mainly arrested SK-OV-3 cells in G2 stage. In addition, molecular docking studies were performed to position compound 8d into the telomerase (5CQG) active site to determine the probable binding model.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) are important targets in the tumor microenvironment for cancer therapy. In the present study, a set of naphthoquinone aromatic amide-oxime derivatives were designed, which stimulated the immune response via IDO1 inhibition and simultaneously displayed powerful antitumor activity against three selected cancer cell lines through suppressing STAT3 signaling. The representative compound 8u bound effectively to IDO1, with greater inhibitory activity relative to the commercial IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear translocation of STAT3. Consistently, in vivo assays demonstrated a higher antiproliferative activity of compound 8u in both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound with dual immunotherapeutic and anticancer efficacy may represent a new generation of highly efficacious drug candidates for cancer therapy.

Cycloaddition reactions such as intramolecular Diels–Alder (IMDA) are extremely important in constructing multicyclic scaffolds with diverse bioactivities. Using MycB as a biomarker, three new polyketides – Chaetolivacines A (1), B (3), and C (4) – with one known compound Myceliothermophin E (2) comprising of decalin and 4-hydroxy-2-pyridones were obtained from the culture of Chaetomium olivaceum SD-80A under the guidance of gene mining. The structures of these compounds were established using detailed 1D, 2D NMR, and high-resolution electron spray ionization mass spectroscopy (HRESIMS) analysis. The relative and absolute configurations of the compounds 1, 3, and 4 were elucidated by NOESY and ECD. The biosynthesis pathways of these compounds were proposed, which involves in three key genes ChaA [polyketide synthase-non-ribosomal peptide synthetases (PKS-NRPS)], ChaB, and ChaC. Compounds 1–4 were tested for their antimicrobial activities, and compounds 2 and 3 showed moderate bioactivity against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) with MIC values of 15.8 and 27.1 μM. The results showed that configuration of C-21 in 3 and 4 is important for anti-SA and anti-MRSA activities. This study reveals the significant potential of the genus Chaetomium in producing new PKS-NRPS, therefore increasing the speed in the mining for new sources of antimicrobial agents.

A new series of millepachine derivative containing aminophosphonate ester moieties were designed and synthesized, and evaluated for their anticancer activities using MTT assay. Among all the compounds, compound 9m exhibited the most potent cytotoxic activity against all tested human cancer cell lines including multidrug resistant phenotype, which inhibited cancer cell growth with IC50 values ranging from 0.85 to 3.09 μM, respectively. In addition, its low cytotoxicity toward human normal liver cells HL-7702 and sensitivity toward to doxorubicin or cisplatin-resistant cells indicated the possibility for cancer therapy. Furthermore, 9m significantly induced cell apoptosis and cell cycle arrest in G2/M phase and dramatically disrupted the microtubule organization. Moreover, a decrease in MMP, an increase in reactive oxygen species (ROS) generation and Bax/Bcl-2 ratio, accompanied by activated caspase-3 and -9, were observed in HepG-2 cells after incubation with 9m, indicating that the mitochondrial pathway was involved in the 9m-mediated apoptosis.

Hypoxia is one of the unique features of tumor physiology. Hypoxia inducible factor (HIF-1α), as a major transcription factor in response to hypoxia, has been considered as a promising tumor-specific target for anticancer therapy. The formation of a hypoxic microenvironment in tumors can decrease the curative effect of cytotoxic chemotherapeutic drugs. To promote the antitumor efficacy of chemotherapy by suppressing hypoxia, we designed and prepared a novel gemcitabine-based drug conjugate (GEM-5) containing a HIF-1α inhibitor (YC-1). As expected, GEM-5 showed excellent antiproliferative activity (IC50 = 0.03 μΜ under hypoxia) and remarkably induced the apoptosis of A2780 cells in vitro. Additionally, western blot analysis demonstrated that GEM-5 significantly down-regulated the expression of HIF-1α and up-regulated the expression of tumor suppressor p53. More importantly, GEM-5 effectively inhibited tumor growth in the A2780 xenograft mouse model and significantly ameliorated tumor hypoxia in vivo. This novel, simple, and effective strategy for overcoming tumor hypoxia and enhancing the antitumor effect of chemotherapeutic drugs has great potential in cancer therapy.

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amide side chains were synthesized and evaluated for inhibition of NF-κB as well as their antitumor effects. These compounds exhibited significant inhibition activity toward NF-κB with IC50 values at micromolar concentrations in the NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound 5Y8 revealed key interactions between 5Y8 and the active site of NF-κB in which the functionalized amide moiety at the C-28 position and an ester group at the C-3 position were important for improving the activity. In particular, compound 5Y8 appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and inducing apoptosis. Mechanistically, compound 5Y8 might trigger the apoptotic signaling pathway. Thus, the rational design of UA derivatives with functionalized aniline or amide side chains offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in the NCI-H460 lung adenocarcinoma cell line.

A series of antitumor agents based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for antiproliferative activity using a panel of cancer cell lines, and the effects and mechanism of apoptosis induction were determined. These compounds exhibited significant selectivity to different cancer cell lines with IC50 values at micromolar concentrations. In particular, compound I-11 appeared to be the most potent compound, with an IC50 = 4.85 ± 1.44 μM against the NCI-H460 cell line, at least partly, by the induction of apoptosis. Mechanistically, compound I-11 induced the activation of caspase-12 and CHOP, which triggered apoptotic signalling via the ROS-dependent endoplasmic reticulum pathway and arrested the cell cycle at the S phase. Thus, we concluded that dipeptide derivatives containing the thiourea moiety terminally functionalized by electron-withdrawing substituents may be potential antitumor agents for further investigation.

In general, carbon materials with high specific surface area (SSA), well-balanced pore size distributions, and appropriate content of heteroatom functionalities are essential to enhance the performance of electric double layer capacitors (EDLCs) for capacitive energy storage. In this study, a low-cost biological waste-stiff silkworm was first used as precursor for the synthesis of well-developed microporous carbon (SSMC) material by simple steps of carbonization and further activation. The SSMC was endowed with ultra-high SSA (2523 m 2 g −1 ), large pore volume (1.37 m 3 g −1 ), and high content of heteroatom functionalities (∼3.5 at% N and ∼5.1 at% O). EDLCs employed SSMC as active material showed high specific capacitance of 304 F g −1 and 256 F g −1 at current densities of 1 A g −1 and 20 A g −1 , respectively, suggesting the good rate capability. Symmetric-two-electrode test in aqueous electrolyte also delivered the specific capacitance of 235 F g −1 with the energy density of ∼7.9 W h kg −1 . The findings confirmed the feasible way that using the eco-friendly biomass raw material to construct high performance capacitive energy storage device.

In this paper, we report an efficient method by high-speed counter-current chromatography for the first separation of four aromatic acids and two analogues with similar structures and polarities from Clematis akebioides. Firstly, the ethyl acetate extract was treated by silica gel column chromatography to enrich the target compounds. And then the fraction with target compounds were purified by high-speed counter-counter chromatography using a two-phase solvent system consisting of chloroform/acetonitrile/water (10:6:4, v/v). The results showed high-speed counter-current chromatography could be a powerful technology for separation of compounds with similar structures and polarities. Besides, it was found acetonitrile could be a good methanol substitutes when a chloroform/methanol/water system could not provide a good separation factor. This study provides a reference for the separation compounds from Clematis akebioides. This article is protected by copyright. All rights reserved

Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.

Ligularia speices are widely used in Asian folk medicines for the treatment of various human diseases. Eremophilane-type sesquiterpenes are abundant and typical secondary metabolites found in this genus. Over 500 eremophilanes reported from members of Ligularia are reviewed in this article together with bioactivity data in an effort to highlight the development in this field.

Several N-aryl maleopimaric acid diimides (3a-3d, 4a-4g) were synthesized and evaluated their topoisomerase I inhibitory activities along with cytotoxicities against NCI, MGC-803, Bel-7404 and Hct-116 cell lines. The pharmacological dates revealed that most of structure analogs exhibited moderate to high levels of anticancer activities against the tested cancer cell lines. Compound 4g with phenylalanine substituent exhibited significant cytotoxicity against MGC-803 and Hct-116 cells (IC 50 was 9.85±1.24 and 8.47±0.95 µM, respectively). All the synthesized compounds exhibited no cytotoxicity against HUVEC cells. In addition, maleopimaric diimides showed stronger cytotoxicity and topoisomerase I inhibitory activity compared to that of maleopimaric acid. Structure–activity relationship study showed that carboxyl and diimide moieties were important to display Topo I inhibitory activities. Further experiments proved that 4g could induce apoptosis of MGC-803 cells. In addition, the further mechanisms of compound 4g-induced apoptosis in MGC-803 cells demonstrated that compound 4g induced the activations of caspase-4, caspase-8 and caspase-3 for causing cell apoptosis, and altered antiand pro-apoptotic proteins. Moreover, cell cycle analysis indicated that the derivative 4g mainly arrested MGC-803 cells in S stage.

To study the chemical constituents of Rubus stans.The chemical constituents were isolated and purified by silica gel and Sephadex LH-20 column chromatography. The structures were identified on the basis of spectroscopic analysis and physicochemical properties.Eleven compounds were isolated and purified from the ethanol extract of Rubus stans. They were identified as β-sitosterol( 1),betulinic acid( 2),euscaphic acid( 3),ursolic acid( 4),corosolic acid( 5),kaempferol( 6),quercetin( 7),2α,3β,19α,23-tetrahydroxy-urs-12-en-28-oic acid( 8),β-daucosterol( 9),quercetin-3-O-β-D-glucoside( 10) and kaempferol-3-O-β-D-6-O-( p-hydroxycinnamoyl)-glucopyranoside( 11).All the compounds are isolated from this plant for the first time.

To study the chemical constituents from the whole plant of Delphinium caeruleum.The chemical constituents were isolated and purified by silica gel and Sephadex LH-20 column chromatography. The structures of the isolated compounds were elucidated by spectroscopic analysis and physicochemical properties.Twelve compounds were isolated and purified from the ethanol extract of Delphinium caeruleum. They were identified as β-sitosterol( 1),kaempferol( 2),quercetin( 3),isovanillic acid( 4),apigenin( 5),luteolin( 6),8-methoxy-5,7,3’,4’-tetrahydroxy-flavone( 7),β-daucosterol( 8),kaempferol-3-O-β-D-glucoside( 9),3,5-dihydroxy-4’-methoxyflavone-7-yl-O-β-D-glucopyranosyl-( 1→4)-α-L-rhamnopyranoside( 10),rutin( 11) and sucrose( 12).Compounds 1 ~ 12 are isolated from this plant for the first time.

Ent‑3α‑formylabieta‑8(14),13(15)‑dien‑16,12β‑olide (EFLDO) is a compound extracted from Euphorbia lunulata Bge exhibiting anti‑proliferative activity in vitro. In the present study, EFLDO was identified to sensitize HepG2 cells to tumor necrosis factor (TNF) superfamily member 10 (TNFSF10)‑induced apoptosis. Liver cancer cells were resistant to TNFSF10; however, EFLDO increased TNFSF10‑induced cancer cell viability inhibition and cell apoptosis induction as assessed by MTT assay and Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide assay, respectively. The western blotting results suggested that treatment with EFLDO increased TNFSF10‑induced upregulation of the protein expression levels of pro‑apoptotic proteins, including BCL2 associated agonist of cell death, BCL2 associated X, apoptosis regulator, caspase‑3 (CASP3) and CASP8. Furthermore, treatment with EFLDO increased TNFSF10‑mediated downregulation of the protein expression level of the anti‑apoptotic protein BCL2 apoptosis regulator. Notably, the increase in the activity of CASP3 was consistent with the western blotting results. Treatment with EFLDO sensitized liver cancer cells to TNFSF10, and apoptosis was induced via the upregulation of TNF receptor superfamily member 10a (TNFRSF10A) and TNFRSF10B in a tumor protein p53 (p53)‑dependent manner, as detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. In addition, p53 was identified to be necessary for EFLDO‑induced sensitivity to TNFSF10, as assessed by western blotting and Annexin V‑FITC assay. Collectively, the present results suggested a novel mechanism underlying EFLDO function in liver cancer. Treatment with EFLDO was able to increase the antitumor effect of TNFSF10 in liver cancer cells in a p53‑dependent manner.

Two novel prenylated kaempferol derivatives (1, 2), together with seven known metabolites were isolated from ethanol extract of fresh Platanus acerifolia bud’s fur by multistep chromatographic processing. Structure of compounds 1 and 2 was confirmed by 1D, 2D NMR spectra and HR-ESI-MS. In addition, compound 1 was further analysed by X-ray crystallography. Anti-proliferative activities in vitro against human breast carcinoma (MCF-7) and human hepatocellular carcinoma (Hep-G2) cell lines for compound 1, 2 and 8 were evaluated. Compound 1 exhibited cytotoxic activity towards MCF-7 and Hep-G2 cell lines with the IC50 values 38.2 and 39.5 μM, respectively. Moreover, compound 2 showed weak cytotoxic activities against the two cell lines.

Accurate calculation of equilibrium formation conditions of hydrates is important for gas storage and separation based on hydrate technology. In this work, the hydrate formation conditions of a synthesized gas mixture in tetra-n-butyl ammonium bromide (TBAB) aqueous solution were measured at temperature ranging from 278.1 to 286.2 K. An inflection point in the P–T curve of hydrate phase equilibria was found. It is suggested that the hydrate structures transformed from semiclathrate hydrates to pure structure I hydrates with an increase in formation temperature. Then a thermodynamic model was proposed for calculating formation conditions of the semiclathrate hydrates formed from the gas mixtures+TBAB aqueous solution. The Patel–Teja equation of state was used to calculate the fugacity of gaseous hydrate former and several correlations were used to calculate the properties of TBAB. Ethylene molecules are supposed not to be able to occupy the dodecahedral small cages in the TBAB semiclathrate hydrates under the experimental P–T conditions. The presented model results show good agreement with the experimental data and the literature data.

Pentacyclic triterpene derivatives possessing polyhydroxyl ring A exhibit many important pharmacological activities. (1β, 2α, 3β, 19β, 23)-1,2,3,19,23-pentahydroxyolean-12-en-28-oic acid (5), a new bioactive phytochemical with tetra-hydroxyl ring A isolated from Euphorbia sieboldiana in our laboratory, showed potential inhibition effects against several cancer cells previously. This study was performed to investigate the underlying mechanisms of action for its antitumor activity. The results showed that compound 5 inhibited dose-/time-dependently cell growth with low toxicity to normal cells and induced apoptosis in cervical cancer cells. Also, compound 5 inhibited the growth and proliferation of HeLa cells and resulted in G1 phase arrest. Furthermore, exposure of cells to compound 5 caused inactivation of the TNF-α-TAK1-IKK-NF-κB axis and inhibition of TNF-α-stimulated NF-κB activity, followed by down-regulation of NF-κB target genes involved in cell apoptosis (Bcl-2) and in the cell cycle and growth (Cyclin D, c-Myc). Additionally, compound 5 significantly suppressed the migration of HeLa cells. In addition, exposure of HeLa cells to compound 5 decreased the activity of NF-κB through the generation of reactive oxygen species (ROS). Collectively, these results suggested that compound 5 exerted potent anticancer effects on HeLa cells in vitro through targeting the ROS-dependent NF-κB signaling cascade and this compound may be a promising anticancer agent for cancer treatment.

To study the apoptosis induced by EFLDO (ent-3α-formylabieta-8(14), 13(15)-dien-16,12β-olide), extracted from the Euphorbia lunulata Bge, in the HepG2 cell line and to study the antitumor activity of this compound in vivo, Cell viability and migration were evaluated with CCK-8 (2-(2-methoxy-4-nitrophenyl)-3- (4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) and wound healing assays, respectively. In addition, the cell cycle was examined using flow cytometry after propidium iodide (PI) staining. Apoptosis was analyzed by using the Annexin V/PI staining assay. Pro-caspase activation and apoptosis protein expression were evaluated by western blotting. A HepG2 xenograft model in nude mice was also established to study the antitumor activity of EFLDO in vivo. Immunohistochemical analysis was used to detect the expression of Ki67 in the tumors in situ. EFLDO could induce dose- and time-dependent apoptosis in HepG2 human hepatic cancer cells. Activation of caspases 3, 8, and 9 played an important role in EFLDO-induced apoptosis in vitro. Decreased levels of Bcl-2 and Survivin and increased level of BAX were also involved in this process. Furthermore, EFLDO could inhibit HepG2 tumor growth in nude mice, and the proliferation characteristics, reflected by the Ki67 index, were suppressed significantly. The results indicated that EFLDO could induce apoptosis in hepatic cancer cells by caspase activation in vitro and suppress tumor growth in vivo.