Four new tirucallane-type triterpenoids from Aphanamixis polystachya.

Four new tirucallane-type triterpenoids, polystanins H-K (1-4), were obtained from the stems and leaves of Aphanamixis polystachya. Their structures were elucidated by analysis of the spectroscopic data and comparison with literature data. Compounds 1 and 2 showed week inhibitory effects against NO production in LPS-stimulated RAW264.7 cells. All the isolates were investigated for their antifungal activities against drug-resistant Candida albicans.

Triterpenoids from the fruits of Aphanamixis polystachya and their inhibitory activities on nitric oxide production.

Nineteen triterpenoids, including five previously unknown (four triucallane-type derivatives and one highly oxidized A, B-seco limonoids), together with fourteen known triterpenoids, were isolated from the fruits of Aphanamixis polystachya. Their structures were elucidated by extensive spectroscopic analysis. All isolates were evaluated their anti-inflammatory activities. The result showed that all compounds inhibit LPS-induced nitric oxide production in RAW264.7 macrophages with their IC50 value ranging from 95 to 1332 uM, and compound 6 exhibited obvious anti-inflammatory activity comparable to that of the positive control, with IC50 values of 94.96 uM.

Two new triterpenoids from the fruits of Aphanamixis polystachya.

Two new triucallane triterpenoids, polystanin F (1) and polystanin G (2), along with eight known compounds (3-10) were isolated from the fruits of Aphanamixis polystachya. Their structures were established on the basis of extensive spectroscopic analysis. Moreover, eight compounds were evaluated for their in vitro cytotoxicity against three cancer cell lines (liver cancer RT112, colon cancer HCT-116 and breast cancer M231) using the MTT method. Compound 7 showed significant cytotoxic activity against HCT-116 with IC50 1.27 µM.

Flower extract of Caragana sinica. ameliorates DSS-induced ulcerative colitis by affecting TLR4/NF-κB and TLR4/MAPK signaling pathway in a mouse model.

OBJECTIVES: This study aimed to find out the protective effects and preliminary mechanisms of the flower extract of Caragana sinica (FEC) on dextran sulfate sodium salt (DSS)-induced colitis. MATERIALS AND METHODS: The ulcerative colitis models of mice induced by 3% DSS were established and treated with FEC. Body weight changes, disease activity index (DAI), colon histopathological score, anti-oxidant ability, and the level of inflammatory cytokines were determined. The expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) were assessed in colonic tissue by immunohistochemical staining. Western blot was used to analyze the expression of TLR4/ nuclear factor kappa-B (NF-κB) and TLR4/ mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. RESULTS: FEC significantly prevented body weight loss and colonic shortening and reduced the disease activity index and histopathological score (P<0.05). Moreover, FEC treatment remarkably down-regulated the levels of myeloperoxidase (MPO), interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) and up-regulated the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and interleukin 10 (IL-10) in the colon of DSS mice (P<0.05). Furthermore, the expression of TLR4/NF-κB and TLR4/MAPK pathway-related proteins was inhibited by FEC (P<0.05). CONCLUSION: Our findings demonstrated that FEC could serve as a potential therapeutic agent for treatment of ulcerative colitis.

Ten picrotoxane-type sesquiterpenoids from the stems of Dendrobium wardianum Warner.

Ten undescribed picrotoxane-type sesquiterpenoids, dendrowardins A-J, together with two known ones, were isolated from the stems of Dendrobium wardianum Warner (Orchidaceae). Dendrowardins A-D feature the unusual 5,2-δ-lactone and additionally dendrowardins C-D are the first examples containing the 11,10-γ-lactone moiety. The structures were established using spectroscopic methods and by comparison with literature data. Further, dendrowardin E, amotin, and aduncin exhibited significant effects of promoting the proliferation on human lens epithelial cells (HLECs) induced by D-galactose.

Sesquiterpenoids from the roots and rhizomes of Valeriana amurensis and their effects on NGF-induced neurite outgrowth in PC12 cells.

Two new sesquiterpenoids, including a kessane-type sesquiterpenoid (1) and one bisabolane derivative (2), together with fourteen known sesquiterpenoids (3-16), were isolated from the roots and rhizomes of Valeriana amurensis. The structures of new compounds were established on the basis of extensive spectroscopic analysis. All isolates were evaluated for their effects on nerve growth factor (NGF)-mediated neurite outgrowth in pheochromocytoma (PC12) cells. As a results, four compounds including 10-12 and 15 showed potent promoting effects at the concentration of 10 µM on NGF-induced neurite outgrowth in PC12 cells with the differentiation rate of 11.84%, 12.21%, 13.77% and 12.16%, respectively.

Two unusual dendrobine-type alkaloids from Dendrobium findlayanum.

Two unusual dendrobine-type alkaloids, findlayines E and F (1, 2), along with five known dendrobine-type alkaloids (3-7), were isolated from the stems of Dendrobium findlayanum Par. et Rchb. f. Compound 1 is the first example of dendrobine-type alkaloids with a 2-ethoxy-2-oxoethyl group attaching to the C-2, and compound 2 is a nor-dendrobine-type alkaloid, featuring a 5-decarboxylated structure. The structures of compounds 1 and 2 were elucidated by means of extensive spectroscopic analyses, and their absolute configuration were confirmed by electronic circular dichroism (ECD) calculations. All isolates were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549 and MCF-7 human cancer cells.

Synthesis and antitumor activity of camptothecin- 4ß-triazolopodophyllotoxin conjugates.

Two new compounds (9 and 10) having a camptothecin (CPT) analog conjugated to the 4ß-azido-4-deoxypodophyllotixin analog by untilizing the copper-catalyzed azide-alkyne cycloadditon (CuAAC) reaction, and were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using the MTT (3-(4,5-dimethyl-thiahiazo-2-yl)-2,5-diphenyltetrazolium bromide) assay. Two novel conjugates shown weak cytotoxicity, compound 10 showed highly potent against HL-60 cell line tested, with IC50 value 17.69 ± 0.19 µM. This compound suggested its potential as anticancer agents for further development. [Formula: see text].

Four new sesquiterpene derivatives from Dendrobium findlayanum.

Three new sesquiterpene glycosides with alloaromadendrane and ylangene-derived type aglycones, named dendrofindlayanosides A-C (1-3), one new cyclopacamphane type sesquiterpene named dendrofindlayanobilin A (4), together with five known compounds have been isolated from stems of Dendrobium findlayanum. Their structures were determined on the basis of spectroscopic and chemical methods.

Design, Synthesis, and Biological Evaluation of Novel Biotinylated Podophyllotoxin Derivatives as Potential Antitumor Agents.

Podophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following human cancer cell lines, SW480, MCF-7, A-549, SMMC-7721, and HL-60 by MTT assay. Most of them exhibited potent cytotoxic effects and compound 15 showed the highest cytotoxic activity among the five cancer cell lines tested, having its IC50 values in the range of 0.13 to 0.84 µM. Apoptosis analysis revealed that compound 15 caused obvious induction of cell apoptosis. Compound 15 significantly down-regulated the expression level of the marker proteins (caspase-3 and PARP) in H1299 and H1975 cells, activated the transcription of IRE1α, increased the expression of GRP78 and XBP-1s, and finally induced apoptosis of H1299 cells. In vivo studies showed that 15 at a dose of 20 mg/kg suppressed tumor growth of S180 cell xenografts in icr mice significantly. Further molecular docking studies suggested that compound 15 could bind well with the ATPase domain of Topoisomerase-II. These data suggest that compound 15 is a promising agent for cancer therapy deserving further research.

Four new monoterpenoids from the whole plants of Valeriana stenoptera.

Four new monoterpenoids, including two new acyclic monoterpenoids (2R, 6R)-2, 6-dimethyl-8-isovaleroxyoctan-1-ol (1) and (2S, 6S)-2, 6-dimethyl-8-isovaleroxyoctan-1-ol (2), as well as two new iridoids stenopterins F-G (3 and 4), together with fifteen known compounds (5-19), were isolated from whole dried material of Valeriana stenoptera. Stenopterin F was the first reported iridoids with n-butoxyl in the Valerianaceae family. The structures of new compounds were established on the basis of extensive spectroscopic analysis.

Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents.

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 0.13 to 21.53 µM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC50 = 0.13-3.31 µM) and compound 18 (IC50 = 0.23-1.48 µM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.

Synthesis and anticancer activity of dimeric podophyllotoxin derivatives.

BACKGROUND: Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of antitumor drugs. Several podophyllotoxin-derived antitumor agents, including etoposide, are currently in clinical use; however, their therapeutic efficacy is often limited due to side effects and the development of resistance by cancer cells. Previous studies have shown that 4ß-1,2,3-triazole derivatives of podophyllotoxin exhibit more potent anticancer activity and better binding to topoisomerase-II than etoposide. The effect of dimerization of such derivatives on the anticancer activity has not been studied. METHODS: Two moieties of podophyllotoxin were linked at the C-4 position via 1,2,3-triazole rings to give a series of novel dimeric podophyllotoxin derivatives. 4ß-Azido-substituted podophyllotoxin derivatives (23 and 24) were coupled with various dipropargyl functionalized linkers by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to provide dimeric products in very good yield. The in vitro anticancer activity of the synthesized compounds was evaluated by MTT assay against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). The normal BEAS-2B (lung) cell line was also included for study in order to evaluate the cancer selectivity of the most active compound as compared with normal cells. RESULTS: A group of 16 dimeric podophyllotoxin derivatives with different linkers were synthesized and structurally characterized. Most compounds do not show significant cytotoxicity (IC50 > 40 mM) against all five cancer cell lines. However, one compound (29) which bears a perbutyrylated glucose residue on the glycerol linker is highly potent against all five cancer cell lines tested, with IC50 values ranging from 0.43 to 3.50 µM. This compound (29) also shows good selectivity towards cancer cell lines as compared with the normal BEAS-2B (lung) cell line, showing selectivity indexes from 4.4 to 35.7. CONCLUSION: The anticancer activity of dimeric podophyllotoxin derivatives is generally speaking not improved as compared to their monomeric counterparts, and the potency of these dimeric derivatives can be largely affected by the nature of the linker between the two moieties. Among the synthesized derivatives, compound 29 is significantly more cytotoxic and selective towards cancer cells than etoposide and cisplatin, which are currently in clinical use. Compound 29 is a promising anticancer drug and needs further studies.

Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists.

The roots and rhizomes of Valeriana jatamansi have long been used as folk medicine in Asia and usually named as "Zhizhuxiang" in Chinese for the treatment of abdominal distention and pain. However, its active ingredients and molecular targets for treatment of abdominal pain remain unrevealed. Inhibitors of Cav2.2 N-type voltage-gated calcium channels (VGCCs) are actively sought after for their potential in treating pain, especially chronic pain. As far as we know, the method used for seeking analgesic active ingredient from plant material has rarely been reported. The analgesic potentials of the EtOH extract (0.01 mg/ml) of the roots and rhizomes of V. jatamansi and its EtOAc, n-BuOH and H2O soluble parts (0.01 mg/ml, respectively) were tested herein on Cav2.2, using whole-oocyte recordings in vitro by tow-electrode voltage clamp. The results indicated that the EtOAc-soluble part exhibited the most potent inhibition of Cav2.2 peak current (20 mv). The EtOAc-soluble part was then subjected to silica gel column chromatography (CC) and giving 9 fractions. Phytochemical studies were carried out by repeated CC and extensive spectroscopic analyses after the fraction (0.01 mg/ml) was identified to be active and got seventeen compounds (1-17). All isolates were then sent for further bioactive verification (1 and 3 at concentration of 10 µM, others at 30 µM). In addition, the selectivity of the active compounds 1 and 3 were tested on various ion channels including Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. The results indicated that compound 1 and 3 (an abundant compound) inhibited Cav2.2 with an EC50 of 3.3 and 4.8 µM, respectively, and had weaker or no effect on Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. Compounds 1 and 3 appear to act as allosteric modulators rather than pore blockers of Cav2.2, which may play crucial role in attenuating nociception. The results of present research indicated that the ethnopharmacological utilization of V. jatamansi for relieving the abdominal distention and pain may mediate through Cav2.2 channel. Our work is the first demonstration of inhibition of Cav2.2 by iridoids, which may provide a fresh source for finding new analgesics.

Seco-Dendrobine-Type Alkaloids and Bioactive Phenolics from Dendrobium findlayanum.

Investigation of the 95% EtOH extract of stems of Dendrobium findlayanum afforded four new seco-dendrobines, findlayines A-D (1-4); two known dendrobines, dendrobine (5) and 2-hydroxydendrobine (6); and four new phenolic compounds, dendrofindlaphenols A-C (7, 9, and 10) and 6″-de-O-methyldendrofindlaphenol A (8). Compounds 1 and 2 are the first seco-dendrobines possessing a seven-membered lactam moiety, with 3 and 4 derived from the oxidative cleavage of the C-2-C-3 bond of dendrobine. The structures were established using spectroscopic methods and by comparison with literature data. The absolute configurations of 1-4 were confirmed via single-crystal X-ray diffraction data. Cytotoxic activity assays against HL-60, SMMC-7721, A-549, MCF-7, and SW480 human cancer cell lines revealed IC50 values ranging from 2.3 to 5.3 µM for compound 7, from 19.4 to 34.4 µM for 8, and from 49.4 to 96.8 µg/mL for the EtOAc extract. An assay of the inhibition of NO production with RAW 264.7 cells indicated that 8 had an IC50 value of 21.4 µM, and the EtOAc extract, 10.5 µg/mL. The EtOAc extract possessed DPPH radical scavenging activity of 69.93% at 100 µg/mL.

Four new glycosides from the stems of Dendrobium fimbriatum Hook.

Four new glucosides, named as gigantol-5-O-ß-d-glucopyranoside (1), 9,10-dihydro-aphyllone A-5-O-ß-d-glucopyranoside (2), ficusal-4-O-ß-d-glucopyranoside (3), botrydiol-15-O-ß-d-glucopyranoside (4), together with eight known compounds (5-12) were isolated from the n-BuOH extract of the stems of Dendrobium fimbriatum Hook. Their structures were elucidated by the analyses of spectroscopic data.

Oleanane-type triterpene saponins from Hydrocotyle nepalensis.

Five new oleanane-type triterpene saponins including steganogenin 3-O-ß-D-glucopyranoside (1), steganogenin 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside (2), steganogenin 3-O-ß-D-glucopyranosyl-(1→2)-ß-D-glucopyranoside (3), chichipegenin 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside (4) and chichipegenin 3-O-ß-D-glucopyranosyl-(1→2)-ß-D-glucopyranoside (5), along with four known oleanane-type triterpenes and triterpene saponins (6-9) were isolated from EtOH extract of the whole plant of Hydrocotyle nepalensis. To the best of our knowledge, oleanane-type triterpenes possessing skeleton with 17, 22-seco-backbone (1-3) are not common in natural products. Compound 8 was isolated as a new natural product. The structures of new compounds were elucidated by extensive spectroscopic methods and chemical evidence. Moreover, the cytotoxic activity of all the isolates against five selected human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) was evaluated and the results indicated that compounds 6 and 7 show stronger cytotoxic activity.

Iridoids and sesquiterpenoids of Valeriana stenoptera and their effects on NGF-induced neurite outgrowth in PC12 cells.

Twenty-one compounds (nine iridoids and twelve sesquiterpenoids), including ten previously unknown (five iridoids and five sesquiterpenoids) were isolated from whole dried material of Valeriana stenoptera. Structures were established on the basis of extensive spectroscopic analysis and the relative stereochemistry of 13-hydroxypatchoulol A was further confirmed by X-ray crystallographic data. All isolates were evaluated for their effects on nerve growth factor (NGF)-mediated neurite outgrowth in pheochromocytoma (PC12) cells and seven compounds showed potent promoting effects.

Synthesis and antitumor activity of novel per-butyrylated glycosides of podophyllotoxin and its derivatives.

A series of perbutyrylated glycosides of podophyllotoxin and its derivatives were synthesized and evaluated for their antitumor activity in vitro. Most of them exhibit cytotoxic activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Among the synthesized compounds, epipodophyllotoxin α-d-galactopyranoside 8b, epipodophyllotoxin α-d-arabinopyranoside 8e, and podophyllotoxin ß-d-glucopyranoside 11a show the highest potency of anticancer activity with their IC50 values ranging from 0.14 to 1.69µM. Structure activity relationship analysis indicates that the type of glycosidic linkage, the configuration at C-4 of the podophyllotoxin scaffold, and the substitution at 4'-position (OH vs OCH3) can all have significant effect on the potency of their anticancer activity. Several compounds are more active than the control drugs Etoposide and Cisplatin, suggesting their potential as anticancer agents for further development.

Iridoids and sesquiterpenoids from the roots of Valeriana jatamansi Jones.

Three new iridoids, jatamanvaltrates R-S (1-2) and jatamanin Q (3), as well as three new sesquiterpenoids, valeriananoids D-E (4, 5) and clovane-2ß-isovaleroxy-9α-ol (6), together with nine known compounds were isolated from the roots of Valeriana jatamansi Jones. Compound 2 was the first reported iridoid with fatty acid esters in the Valerianaceae family. The structures of new compounds were established on the basis of extensive spectroscopic analysis. Moreover, all the isolates were evaluated for inhibitory activity on acetylcholinesterase (AChE).