Brunonianines D-F, three new C19-diterpenoid alkaloids from the Delphinium brunonianum, with therapeutic effect on ovarian cancer in vitro and in vivo.

The current standard treatment for ovarian cancer consists of surgery to reduce the size of the tumor, followed by treatment with chemotherapeutic drugs, which have major side effects. Therefore, finding a new natural product drug with fewer side effects is a strategy. Delphinium brunonianum (D. brunonianum) is a traditional Tibetan medicine, mainly from southern Tibet, China, whereas the chemical constituents in this plant remain elusive. The major metabolites in the dichloromethane fraction of D. brunonianum were analyzed and purified by HPLC and various column chromatography techniques. Nine diterpenoid alkaloids (1-9) and one amide alkaloid (10) were isolated from D. brunonianum, including three novel C19-type diterpenoid alkaloids (Brunonianines D-F) (1-3). Their structures were elucidated by 1D/2D NMR, HR-ESI-MS and single-crystal X-ray diffraction analyses. All compounds were evaluated for toxicity in four tumor cell lines. Most of the compounds exhibited potent inhibitory effects on Skov-3 cell lines, with IC50 values ranging from 2.57 to 8.05 µM. The western blotting experiment was used to further analyze the expression levels of molecules in the Bax/Bcl-2/Caspase-3 signaling pathway for compound 1. Molecular docking was performed to predict the binding modes of Brunonianine D with target proteins. In vivo experiments were also performed and evaluated in real time by monitoring the size of the Skov-3 tumor. Additionally, tumor H&E staining and the TUNEL assay used to evaluate anti-tumor effects.

Chemical constituents of Rubia tibetica Hook. f. from Tibetan medicine and cytotoxic activity evaluation.

Two unprecedented quinone compounds Rubiaxylm A (1) and Rubiaxylm B (2), along with fifteen known anthraquinones (3-17) were isolated and characterized from the roots of Rubia tibetica in Tibetan medicine. Their structures were identified through comprehensive analyses of 1D/2D NMR as well as HR-ESIMS data. Furthermore, all separated compounds were evaluated for their cytotoxic activity on A549, Caco-2, MDA-MB-231 and Skov-3 cell lines. In particular, compound 2 effectively inhibited MDA-MB-231 cells with an IC50 value of 8.15 ± 0.20 µM. Subsequently, the anti-tumor mechanism of 2 was investigated by flow cytometry, JC-1 staining, cell scratching and cell colony. These results indicated that compound 2 could inhibit the proliferation of MDA-MB-231 cells by arresting cells in the G1 phase.

Brunonianines A-C, C20-diterpenoid alkaloids with cyano group from Delphinium brunonianum Royle.

Cyano tends to have better biological activity, but it is rarely reported in natural products, especially in the C20-diterpene alkaloids. Herein, three unprecedented C20-diterpenoid alkaloids, brunonianines A-C (1-3), possessing rare cyano functional group as well as an atisine backbone constructed from a phenethyl substituent and a tetrahydropyran ring, along with four C19-alkaloids (4-7) and one amide alkaloids (8), were isolated from the whole plant of Delphinium brunonianum Royle. Compounds 1-3 are also the first atisine type diterpenoid alkaloids with cyano group obtained from nature. The structures of the previously undescribed compounds were elucidated by HR-ESI-MS, 1D/2D NMR spectroscopic data and electronic circular dichroism calculations and single-crystal X-ray diffraction. Reasonable speculations have also been made regarding the biogenic synthetic pathways of compounds 1-3. In addition, the inhibitory activity of all compounds was also tested against four tumor lines: A549, Caco-2, H460 and Skov-3, where compound 2 (IC50 2.20 ± 0.21 µM) showed better inhibitory activity against Skov-3 cells than the hydroxycamptothecin. Using flow cytometry, cell staining, migration and invasion analysis, and Western blot, compound 2 was found to arrest cells in the G2/M phase and was able to effectively inhibit cell motility to achieve potent anti-tumor effects. In addition, compound 2 can effectively induce apoptosis by activating the Bax/Bcl-2/Caspase-3 signaling pathway.

Two new alkaloids from Tibetan medicine of Hypecoum leptocarpum.

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).[Formula: see text].

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

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.

Anti-proliferative effects of diterpenoids from Sagittaria trifolia L. tubers on colon cancer cells by targeting the NF-κB pathway.

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/ß 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.

NF-κB inhibitory and cytotoxic activities of hexacyclic triterpene acid constituents from Glechoma longituba.

BACKGROUND: Non-Small-Cell Lung Cancer (NSCLC) is the most-frequent cause of cancer death, and novel chemotherapeutic drugs for treating NSCLC are urgently needed. 2α, 3α, 23-trihydroxy-13α, 27-cyclours-11-en-28-oic acid (euscaphic acid G) is a new hexacyclic triterpene acid isolated by our group from Glechoma longituba (Nakai) Kupr. However, the underlying mechanisms responsible for the anticancer effects of hexacyclic triterpene acid have not been elucidated. PURPOSE: In the present work, we evaluated growth inhibitory effect of the new isolated hexacyclic triterpene acid and explored the underlying molecular mechanisms. METHODS/STUDY DESIGNS: Herbs were extracted and constituents were purified by chromatographic separation, including silica gel, ODS, MCI, Sephadex LH-20 and preparative HPLC. The compound structures were elucidated by the use of UV, NMR and MS spectral data. The anticancer activity of euscaphic acid G was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. To display the possible mechanism of euscaphic acid G on NCI-H460 cells, RT-PCR, immunofluorescence and Western blot analysis were carried out. RESULTS: A new hexacyclic triterpene acid, euscaphic acid G, together with fifteen known triterpenoids, was isolated from the aerial parts of G. longituba. Our results showed that euscaphic acid G exerted strong anti-proliferative activity against NCI-H460 cells in a concentration- and time-dependent manner. Flow cytometry demonstrated euscaphic acid G arrested the cell cycle at G1 phase, induced cellular apoptosis, accompanied by ROS generation and mitochondrial membrane potential reduction. Mechanistic studies revealed that euscaphic acid G treatment inhibited IKKα/ß phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. CONCLUSION: In conclusion, these results suggested that euscaphic acid G from G. longituba showed potential anticancer effects against lung cancer cells via inducing cell cycle arrest and apoptosis, at least partly, through NF-κB signaling pathways.

Synthesis and discovery of asiatic acid based 1,2,3-triazole derivatives as antitumor agents blocking NF-κB activation and cell migration.

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 IC50 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 (IC50 = 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 pentacyclic triterpene derivative possessing polyhydroxyl ring A suppresses growth of HeLa cells by reactive oxygen species-dependent NF-κB pathway.

Pentacyclic triterpene derivatives possessing polyhydroxyl ring A exhibit many important pharmacological activities. (1ß, 2α, 3ß, 19ß, 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.

Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB.

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50 values ranged from 5.22 to 8.95 µM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity.

The chemistry and pharmacology of Ligularia przewalskii: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligularia przewalskii (Maxim.) Diels (LP) (called zhangyetuowu in Chinese), is generally found in moist forest areas in the western regions of China. The root, leaves and flower of LP are utilized as a common traditional medicine in China. It has been utilized conventionally in herbal remedies for the remedy of haemoptysis, asthma, pulmonary phthisis, jaundice hepatitis, food poisoning, bronchitis, cough, fever, wound healing, measles, carbuncle, swelling and phlegm diseases. AIM OF THE STUDY: The review aims to provide a systematic summary of LP and to reveal the correlation between the traditional uses and pharmacological activities in order to provide updated, comprehensive and categorized information and identify the therapeutic potential for its use as a new medicine. MATERIALS AND METHODS: The relevant data were searched by using the keywords "Ligularia przewalskii" "phytochemistry", "pharmacology", "Traditional uses", and "Toxicity" in "Scopus", "Scifinder", "Springer", "Pubmed", "Wiley", "Web of Science", "China Knowledge Resource Integrated databases (CNKI)", "Ph.D." and "M.Sc. dissertations", and a hand-search was done to acquire peer-reviewed articles and reports about LP. The plant taxonomy was validated by the databases "The Plant List", "Flora Reipublicae Popularis Sinicae", "A Collection of Qinghai Economic Plants", "Inner Mongolia plant medicine Chi", Zhonghua-bencao and the Standard of Chinese herbal medicine in Gansu. RESULTS: Based on the traditional uses, the chemical nature and biological effects of LP have been the focus of research. In modern research, approximately seventy-six secondary metabolites, including thirty-eight terpenoids, nine benzofuran derivatives, seven flavonoids, ten sterols and others, were isolated from this plant. They exhibit anti-inflammatory, antioxidative, anti-bacterial and anti-tumour effects, and so on. Currently, there is no report on the toxicity of LP, but hepatotoxic pyrrolizidine alkaloids (HPA) were first detected with LC/MSn in LP, and they have potential hepatotoxicity. CONCLUSIONS: The lung-moistening, cough-relieving and phlegm-resolving actions of the root of LP are attributed to the anti-inflammatory properties of flavonoids and terpenoids. The heat-clearing, dampness-removing and gallbladder-normalizing (to cure jaundice) actions of the flowers of LP are based on the anti-inflammatory, antioxidant and hepatoprotective activity properties of terpenoids, flavonoids and sterols. The Traditional Chinese Medicine (TCM) characteristics of LP (bitter flavour) corroborate its potent anti-inflammatory effects. In addition, the remarkable anti-inflammatory and antioxidant capacities of LP contribute to its anti-tumour and antitussive activities. Many conventional uses of LP have now been validated by modernized pharmacological research. For future research, further phytochemical and biological studies need to be conducted on LP, In particular, the safety, mechanism of action and efficacy of LP could be of future research interest before beginning clinical trials. More in vivo experiments and clinical studies are encouraged to further clarify the relation between traditional uses and modern applications. Regarding the roots, leaves and flowers of LP, their chemical compositions and clinical effects should be compared. The information on LP will be helpful in providing and identifying its therapeutic potential and economic value for its use as a new medicine in the future.

16-O-caffeoyl-16-hydroxylhexadecanoic acid, a medicinal plant-derived phenylpropanoid, induces apoptosis in human hepatocarcinoma cells through ROS-dependent endoplasmic reticulum stress.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and novel chemotherapeutic drugs for treating HCC are urgently needed. 16-O-caffeoyl-16-hydroxylhexadecanoic acid (CHHA) is a new phenylpropanoid isolated by our group from Euphorbia nematocypha which is commonly used to treat solid tumors. However, the underlying mechanisms responsible for the CHHA-induced apoptosis in cancer cells, particularly in HCC, remain unknown. PURPOSE: In the present work, we evaluated the growth inhibitory effect of CHHA on HCC cells and explored the underlying molecular mechanisms. METHODS/STUDY DESIGNS: The anti-proliferative activity of CHHA was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. ER localization was performed by ER-tracker red staining. The effect of CHHA on the expression of mRNA in HCC cells was detected by RT-PCR. The potential mechanisms for proteins level in ER pathway and apoptosis were analyzed by Western blot. RESULTS: Our results showed that CHHA exerted strong anti-proliferative activity against both HepG2 and Bel-7402 cells in a concentration- and time-dependent manner. Mechanistic studies demonstrated that CHHA induced apoptosis through mitochondrial apoptotic pathway, and arrested the cell cycle at G1 phase. CHHA was also found to induce endoplasmic reticulum (ER) stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of GRP78, CHOP, caspase-12 and p-PERK. Inhibition of endoplasmic reticulum stress by salubrinal pretreatment could suppress both apoptosis and ER stress, indicating that ER stress induction contributes to apoptosis and is required for the latter. Besides, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by CHHA and reversed CHHA-stimulated the expression of ER markers. CONCLUSION: In conclusion, CHHA inhibited HCC cell growth and induced apoptosis through mitochondria-mediated pathway and ROS-mediated endoplasmic reticulum stress. This provides molecular bases for developing CHHA into a drug candidate for the treatment of HCC.

EFLDO induces apoptosis in hepatic cancer cells by caspase activation in vitro and suppresses tumor growth in vivo.

To study the apoptosis induced by EFLDO (ent-3α-formylabieta-8(14), 13(15)-dien-16,12ß-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.

A new aromatic glycoside and its anti-proliferative activities from the leaves of Bergenia purpurascens.

Chemical investigation of the ethanolic extracts of the dried leaves of Bergenia purpurascens led to the isolation and identification of a new aromatic glycoside, 1-O-ß-D-glucopyranosyl-2-methoxy-3-hydroxyl-phenylethene (1), along with other 19 known compounds (2-20). The structure of compound 1 was determined by a detailed analysis using various analytical techniques, including 1D and 2D NMR. In vitro anti-proliferative activities of compound 1 on five human cancer cell lines were evaluated. The results showed that compound 1 possessed the most potent effects with the IC50 values of 14.36 ± 1.04 µM against T24 cells. The further bioactivity analysis showed that compound 1 induced apoptosis of T24 cells, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activation of caspase-3 for causing cell apoptosis. The present investigation illustrated compound 1 might be used as a potential antitumour chemotherapy candidate.

Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation.

A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration.

Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities.

Three new lupane-triterpenoids (1-3) along with six known compounds (4-9) were isolated from the ethanolic extract of whole plant of Potentilla discolor Bunge. The structures of Compounds 1-3 were established by extensive 1D and 2D NMR together with other spectrum analysis, indicating that their C-27 positions were highly oxygenated, which were rarely found in nature. Their in vitro anti-proliferative activities against HepG-2, MCF-7 and T-84 cell lines were evaluated by Cell Counting Kit-8 (CCK-8) assay, and the results showed different activities for three cell lines with IC50 values ranging from 17.84 to 40.64 µM. In addition, the results from Hoechst 33258 and AO/EB staining as well as annexinV-FITC assays exhibited Compound 1 caused a markedly increased HepG-2 cellular apoptosis in a dose-dependent manner. The further mechanisms of Compound 1-induced cellular apoptosis were confirmed that 1 induced the production of ROS and the alteration of pro- and anti-apoptotic proteins, which led to the dysfunction of mitochondria and activation of caspase-9 and caspase-3 and finally caused cellular apoptosis. These results would be useful in search for new potential antitumor agents and for developing semisynthetic lupane-triterpenoid derivatives with high antitumor activity.

Side chain-functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block the nuclear factor-kappa B (NF-κB) pathway and cell proliferation.

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.

Terminal functionalized thiourea-containing dipeptides as multidrug-resistance reversers that target 20S proteasome and cell proliferation.

A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the ß5-subunit of the human 20S proteasome with IC50 values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity. In particular, compound 6i 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 inhibition of the activity of 20S proteasome and induce apoptosis. In addition, 6i-induced apoptosis was significantly facilitated in NCI-H460/DOX cells that had been pretreated with inhibitors of P-gp. Mechanistically, compound 6i might trigger apoptotic signalling pathway. Thus, we conclude that dipeptide derivatives containing the thiourea moiety may be the potential inhibitors of proteasome with the ability to reverse multidrug resistance.

Chemical Constituents of the Aerial Parts of Euphorbia nematocypha.

Chemical constituents of the dried aerial parts of Euphorbia nematocypha were investigated. A new oleanane triterpenoid, trans, trans-2',4'- hexadienedioicacid-1'-ß-amyrin ester (1), together with, ß-amyrin (2), ß-amyrin acetate (3), betulinic acid (4), ellagic acid (5), oleanolic acid (6), ß-sitosterol (7), kaempferol (8), quercetin (9), lupeol (10) and pseudo-taraxasterol (11) were isolated from the methylene chloride extract. Their structures were elucidated on the basis of extensive spectroscopic (1D- & 2D-NMR) and ESI-MS analysis and comparison with data reported in the literature. The new isolated triterpenoid showed moderate cytotoxic activities against HeLa and MCF-7cell lines.

Two novel prenylated kaempferol derivatives from fresh bud's fur of Platanus acerifolia and their anti-proliferative activities.

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.