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A photoinduced intramolecular cyclization of allyl acrylates to synthesize fully substituted spiro-γ-butyrolactone compounds is described. The reaction is believed to proceed through an intramolecular hydrogen abstraction strategy.

Autophagy is an intracellular lysosomal/vacuolar degradation system, in which the inner cytoplasmic cell membrane is degraded by the lysosomal hydrolases, followed by the resulting products released back into the cytosol. It is involved in many physiological processes which are crucial for cell growth and survival. However, disturbance in the autophagic process is often associated with a variety of human diseases, such as cancer. Breast cancer is one of the most malignant tumors characterized by the imbalanced cell proliferation, apoptosis as well as disordered autophagy regulation. The alterations of autophagy related genes or protein levels in breast cancer cells also suggested a potential implication of autophagy in breast cancer development and progression. Many natural products had been reported as potential anti-cancer agents or being considered as direct or indirect sources of new chemotherapy adjuvants to enhance the efficacy or to ameliorate the side effects through the modulation of autophagy. Investigation of the underlying mechanism of these compounds could be crucial for the development of new therapeutic or chemopreventive options for breast cancer treatment. In this review, a summary of those natural products that can regulate autophagy in breast cancer is presented and the potential value of such autophagy modulators on the development of anti-cancer drugs is also discussed.

Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apoptosis. In this study, LK-A inhibited ESCC cells viability and induced G2/M cell cycle arrest. Moreover, LK-A was also highly effective in a KYSE-30 xenograft nude mouse model. Treatment with Z-VAD(OMe)-FMK partially attenuated LK-A-induced apoptosis. LK-A significantly induced reactive oxygen species (ROS) production in ESCC cells, and LK-A-induced apoptosis was attenuated by the ROS scavenger N-acetyl cysteine (NAC). Furthermore, we found that treatment with LK-A activated both the JNK and p38 MAPK signaling pathways, resulting in increases in ROS levels and apoptosis induction. Taken together, these findings indicate that LK-A exerts novel anti-tumor effects in ESCC cells by activating the JNK and p38 MAPK pathways and inducing increases in ROS production, which suggest that the compound may have potential as a clinical therapeutic agent.

Sixteen dibenzocyclooctadiene lignans, including eight new ones, kadheterins A-H (1-8), and a new natural product, 9-benzoyloxy-gomisin B (9), were isolated from the stems of K. heteroclita. The structures of 1-9 were elucidated by extensive spectroscopic methods, and their absolute configurations were determined by combining CD with ROESY experiments. Additionally, the absolute configuration of 1 was further confirmed by single crystal X-ray crystallographic analysis. In vitro activity assays showed that 1 exhibited moderate cytotoxicity against HL-60 with IC50 value at 14.59μM.

On the basis of One Strain/Many Compounds (OSMAC) strategy, five new polyketides, named phomopsiketones A-C (1–3), (10S)-10-O-β-D-4′-methoxymannopyranosyldiaporthin (7), and clearanol H (10), and two new natural products, 4 and 5, along with three known ones, 6, 8 and 9, were isolated from an endophytic fungus, Phomopsis sp. sh917, harbored in stems of Isodon eriocalyx var. laxiflora. Their structures were elucidated by spectroscopic methods. The absolute configurations of 1, 3, and 7 were further confirmed by single crystal X-ray diffraction experiment. Compounds 2, 4, 6, 9 and 10 were assigned absolute configurations on the basis of circular dichroism (CD) or optical rotation (OR) data comparison. In addition, antiangiogenic activity of compounds 2, 3, 5, and 6 were evaluated by using human umbilical vascular endothelial cells (HUVECs) in a cell-culture model of angiogenesis. Especially, compound 6 sufficiently inhibited vascular endothelial growth factor (VEGF)-induced angiogenic processes in vitro, including migration, invasion, and tube formation of HUVECs.

Systematic phytochemical investigation on the stems of Kadsura coccinea resulted in the isolation of eleven new lanostane-type triterpenoids, named kadcoccinones G–Q (1–11), together with two known structural analogues, kadpolysperin M (12) and abiesatrine D (13). Their structures were characterized on the basis of comprehensive spectroscopic methods, and the absolute configuration of 1 was ascertained by single-crystal X-ray diffraction. Structurally, compounds 1/2, 4/5, and 6/7 were three pairs of C-12 epimers, respectively. Additionally, compounds 1–11 were evaluated for their in vitro cytotoxicity against the human tumor HL-60, SMMC-772, A-549, MCF-7, SW-480, and HeLa cell lines using the MTS viability assay.

Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol-based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. Cancer Res; 77(4); 926–36. ©2016 AACR.

Cancer stem cells (CSCs) are a small proportion of tumor cells that may be responsible for tumor metastasis and recurrence. Our recent research indicated that longikaurin A (LK-A) exhibited anti-tumor activity in nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Here, we further investigated whether LK-A could suppress the stemness of NPC cells. Sphere formation assay was used to assess the self-renewal ability of the cells treated with LK-A. Side population (SP) was determined by flow cytometry to measure the influence of LK-A on NPC SPs. The expression of the c-myc and fibronectin was detected by western blotting. The cytotoxicity of LK-A in combination with cisplatin to NPC cells was determined by MTT assay. Colony formation assay was used to verify whether LK-A could sensitize NPC cells to radiation and reverse the radiotherapy resistance. In the present study, we found that LK-A reduced the number and size of spheroid formation and decreased the SP cell percentage of the S18 cell line at a low concentration. Furthermore, LK-A treatment downregulated the expression of c-myc and fibronectin in NPC cell lines. Moreover, LK-A could significantly enhance the chemotherapeutic and radiotherapeutic sensitivity of NPC cell lines and reverse acquired radiotherapy resistance of Sune2-IR. Our data revealed that LK-A could suppress the stemness of NPC cells and may enhance the efficacy of radiotherapy and chemotherapy.

Nine 7,20-epoxy-ent-kaurane diterpenoids (15-acetylmegathyrin B, serrin E, 14β-hydroxyrabdocoestin A, serrin F, serrin G, 11-epi-rabdocoestin A, serrin H, serrin I, and 15-acetylenanderianin N), along with seven known ones, were isolated from the aerial parts of Isodon serra. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configuration of 15-acetylmegathyrin B was determined by signal-crystal X-ray diffraction. All of these compounds were evaluated for their cytotoxic activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480). Serrin F, rabdocoestin B and 1α,11β-dihydroxy-1α,11β-acetonide-7α,20-epoxy-ent-kaur-16-en-15-one showed cytotoxic activities against all cell lines, with IC50 values ranging from 0.7 to 4.6 μM; serrin F also strongly inhibited NO production in LPS-stimulated RAW264.7 cells. Otherwise, 14β-hydroxyrabdocoestin A, serrins H and I, as well as enanderianin N and megathyrin B, also exhibited inhibitory effects towards NO production, while no cytotoxicity against five cell lines was detected.

// Xunian Zhou 1, 2 , Grace Gar-Lee Yue 2, 3 , Minghua Liu 1 , Zhili Zuo 4 , Julia Kin-Ming Lee 2, 3 , Mingyue Li 1 , Stephen Kwok-Wing Tsui 1 , Kwok-Pui Fung 1, 2, 3 , Handong Sun 4 , Jianxin Pu 4 , Clara Bik-San Lau 2, 3 1 School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China 2 Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China Correspondence to: Clara Bik-San Lau, email: claralau@cuhk.edu.hk Jianxin Pu, email: pujianxin@mail.kib.ac.cn Keywords: Eriocalyxin B, angiogenesis, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), breast cancer Received: April 23, 2016 Accepted: October 02, 2016 Published: October 14, 2016 ABSTRACT Eriocalyxin B (EriB), a natural ent -kaurane diterpenoid isolated from the plant Isodon eriocalyx var. laxiflora , has emerged as a promising anticancer agent. The effects of EriB on angiogenesis were explored in the present study. Here we demonstrated that the subintestinal vein formation was significantly inhibited by EriB treatment (10, 15 μM) in zebrafish embryos, which was resulted from the alteration of various angiogenic genes as shown in transcriptome profiling. In human umbilical vein endothelial cells, EriB treatment (50, 100 nM) could significantly block vascular endothelial growth factors (VEGF)-induced cell proliferation, tube formation, cell migration and cell invasion. Furthermore, EriB also caused G1 phase cell cycle arrest which was correlated with the down-regulation of the cyclin D1 and CDK4 leading to the inhibition of phosphorylated retinoblastoma protein expression. Investigation of the signal transduction revealed that EriB inhibited VEGF-induced phosphorylation of VEGF receptor-2 via the interaction with the ATP-binding sites according to the molecular docking simulations. The suppression of VEGFR-2 downstream signal transduction cascades was also observed. EriB was showed to inhibit new blood vessel formation in Matrigel plug model and mouse 4T1 breast tumor model. EriB (5 mg/kg/day) treatment was able to decrease tumor vascularization and suppress tumor growth and angiogenesis. Taken together, our findings suggested that EriB is a novel inhibitor of angiogenesis through modulating VEGFR-2 signaling pathway, which could be developed as a promising anti-angiogenic agent for treatment of angiogenesis-related human diseases, such as cancer.

Four new triterpenoids, propindilactone T (1), propindilactone U (2), changnanic acid 3-methyl ester (3) and schipropinic. acid (4), together with five known ones (5-9), were isolated and identified from the stems and leaves of Schisandra propinqua var. propinqua; their structures were determined based on spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was confirmed by X-ray analysis. Compounds 1, 2, and 4-9 were tested for their cytotoxic activities against five human tumor cell lines; all were inactive except for 8, which showed weak activity against some of the cell lines.

Four new diterpenoids, phyllostachysins I–L (1–4), along with a known one, hebeiabinin B (5), were isolated from the aerial parts of Isodon phyllostachys (I. phyllostachys). Compounds 1 and 2 feature an ent-kaurane backbone, and 3, 4 and 5 bear an ent-abietane skeleton. Their structures were elucidated by means of spectroscopic analysis. Compounds 3 and 4 exhibited significant cytotoxic activity against human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW-480), and strongly inhibited NO production in LPS-stimulated RAW264.7 cells.

YinHuang drop pill (YHDP) is a new preparation, derived from the traditional YinHuang (YH) decoction. Since drop pills are one of the newly developed forms of Chinese patent drugs, not much research has been done regarding the quality and efficacy. This study aims to establish a comprehensive quantitative analysis of the chemical profile of YHDP. ultra high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was used to identify 34 non-sugar small molecules including 15 flavonoids, 9 phenolic acids, 5 saponins, 1 iridoid, and 4 iridoid glycosides in YHDP samples, and 26 of them were quantitatively determined. Sugar composition of YHDP in terms of fructose, glucose and sucrose was examined via a high performance liquid chromatography-evaporative light scattering detector on an amide column (HPLC-NH2P-ELSD). Macromolecules were examined by high performance gel permeation chromatography coupled with ELSD (HPGPC-ELSD). The content of the drop pill's skeleton component PEG-4000 was also quantified via ultra-high performance liquid chromatography coupled with charged aerosol detector (UHPLC-CAD). The results showed that up to 73% (w/w) of YHDP could be quantitatively determined. Small molecules accounted for approximately 5%, PEG-4000 represented 68%, while no sugars or macromolecules were found. Furthermore, YHDP showed no significant differences in terms of daily dosage, compared to YinHuang granules and YinHuang oral liquid; however, it has a higher small molecules content compared to YinHuang lozenge.

Twenty new neo-clerodane type diterpenoids, scutefolides G1-S (1-20), were isolated from the 70 % aqueous acetone extract of the aerial parts of Scutellaria coleifolia. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of 1, 2, 7, 8, 14 and 15 were determined by means of the CD exciton chirality method. Compounds 1, 2, 5, 7, 8, 12, 14, 15, 18 and 19 were evaluated for their cytotoxic activities against four human cancer cell lines, and anti-bacterial activities against methicillin-resistant Staphylococcus aureus.

Although 1,25‑dihydroxyvitamin D3 (VD3) is regarded as a promising inducing agent for leukemia cell differentiation, it is not as effective an agent as all‑trans‑retinoic acid, and its usefulness is also limited by the adverse effects of hypercalcemia. The aim of the present study was to determine whether combining VD3 with adenanthin, a peroxiresoxin I (Prx I)‑targeting natural compound, improves the efficacy of VD3. Cell viability was assessed using a trypan blue exclusion assay and flow cytometry was used to evaluate the expression of cell surface markers, CD11b/CD14, and the level of reactive oxygen species (ROS). Wright's staining was used to examine morphological changes and RNA‑interference was used to knockdown Prx I and p65 gene expression. Protein expression was determined by western blot analysis. The results demonstrated that adenanthin markedly enhanced VD3‑induced cell differentiation of leukemia NB4 cells, as evidenced by the increased percentage of CD11b‑ and CD14‑positive cells, the mature morphology of the monocytes and the increased phagocytic ability. Consistent with these results, knockdown of Prx I, but not nuclear factor‑κB (p65), enhanced VD3‑induced cell differentiation. The combinatorial effects of adenanthin and VD3 were shown to be associated with the ROS‑CCAAT‑enhancer‑binding protein (C/EBP)β axis, since N‑acetylcysteine, a ROS scavenger, was able to abrogate the differentiation‑enhancing effects of adenanthin, and the knockdown of C/EBPβ also inhibited the combinatorial effects of adenanthin and VD3. In addition, co‑treatment with adenanthin and VD3 was able to induce differentiation in other non‑acute promyelocytic leukemia cells and primary leukemia cells. In conclusion, the results of the present study revealed a novel role for Prx I in VD3‑induced cell differentiation, and suggested that targeting Prx I may represent a novel strategy to enhance VD3‑induced leukemia cell differentiation.

Thirty-two enmein-type ent-kaurane diterpenoids, including 13 new compounds, were isolated from the aerial parts of Isodon phyllostachys. Compounds 1 and 2 are the first examples of 3,20:6,20-diepoxyenmein-type ent-kauranoids, and the structures of these new compounds were established mainly by analyzing NMR and HREIMS data. The absolute configurations of 1 and 8 and the relative configuration of 9 were determined using single-crystal X-ray diffraction. Compounds 11, 15, 20, and 21 were active against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), with IC50 values ranging from 1.2 to 5.0 μM. Compounds 3, 11, 15, 17, 20, 21, 25, and 29 strongly inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 0.74 to 4.93 μM.

Penicilfuranone A (1), a novel furancarboxylic acid, and its proposed biosynthetic precursor, gregatin A (2), were isolated from the cultures of the fungus Penicillium sp. sh18 endophytic to the stems of Isodon eriocalyx var. laxiflora guided by HPLC-MS. X-ray crystallography was applied to the structure determination of furancarboxylic acid for the first time, allowing unambiguous assignment of 1. Penicilfuranone A displays a significant antifibrotic effect in activated hepatic stellate cells via negative regulation of transforming growth factor-β (TGF-β)/Smad signaling.

Lancolide E (1) featuring a complex tetracyclo[5.4.0.0(2,4).0(3,7)]undecane-bridged system that is constructed by an eight-, a three-, and two five-membered carbon rings in a sterically congested region was obtained in trace amounts from a "talented" schinortriterpenoid producer Schisandra lancifolia. Its structure was fully characterized by combining 2D NMR spectroscopy, theoretical calculations, and X-ray diffraction analysis. The biogenetic pathway of 1 was proposed to involve a Prins cyclization.

In this report, a new cytotoxic group, a 15-oxo-16 alpha-H-17-methoxy (or ethoxy)- unit, was suggested from the structure-activity relationship analyses of 39 ent-kaurane diterpenoids, including 17 new compounds (neolaxiflorins I-Y, 1-17) isolated from the leaves of Isodon eriocalyx var. laxiflora using an in vitro cytotoxicity assay against HL-60, SMMC-7721, A-549, MCF-7, and SW-480 human cancer cell lines. This discovery is counter to the rule that the alpha,beta-unsaturated ketone (C-15-C-16-C-17) unit is indispensable for cytotoxicity of the ent-kauranoids. Furthermore, portions of the isolates exhibited inhibitory activity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages. The NF-kappa B inhibitory activity assay suggests a potential novel cytotoxic mechanism for compounds 9 and 22. (C) 2015 Elsevier Ltd. All rights reserved.

Four new ent-kaurene diterpenoids, phyllostachysins M–P (1–4) have been isolated from the aerial parts of Isodon phyllostachys. Compound 1 features a novel dihydro-2H-pyran ring motif, which was formed by an unusual cleavage in ring-A. 2 and 3 bear a rare 20-nor-ent-kaurene structure, but 4 has a rare 7,20-cyclo-ent-kaurene skeleton. Their structures were elucidated on the basis of extensive spectroscopic analyses. Compounds 1, 3, and 4 were evaluated for their cytotoxic activity against five human tumor cell lines.

The phytochemical investigation on 1 g of materials from Gypsoplaca macrophylla (Zahlbr.) Timdal resulted in the discovery of gypmacrophin A, a rare pentacyclic sesterterpenoid; brialmontin III, a new polysubstituted depside and two known ones, brialmontins I and II. The structure and absolute configurations of gypmacrophin A were elucidated by spectroscopic analyses and computational methods. Gypmacrophin A showed weak inhibition of AchE with an IC50 value of 32.03 μM. The four compounds provided new chemical evidence for G. macrophylla identification.

The present study was designed to determine the chemical constituents of EtOAc extracts of the aerial parts of Isodon wikstroemioides. Compounds 1-8 were isolated and purified by normal-phase silica gel and reversed-phase C-18 silica gel column chromatography and HPLC. Their structures were elucidated by extensive spectroscopic methods. Most of them were evaluated for their in vitro cytotoxicity against human cancer HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cells and their inhibitory activity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages. Among the eight 11, 20-epoxy-ent-kauranoids isolated, compounds 1-6 (isowikstroemins H-M) were new diterpenoids. Compounds 1, 3, and 7 exhibited significant cytotoxicity with IC50 values ranging from (0.84 +/- 0.02) to (4.09 +/- 0.34) mu mol.L-1, while compounds 4 and 5 showed selective cytotoxicity. In addition, compounds 1, 3, 4, and 7 exhibited inhibitory activity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages. These results provide a basis for future development of these compounds as anti-cancer and anti-inflammatory agents.

Two compounds belonging to a new group of diterpene alkaloids, kaurines A and B (1 and 2), and an alkaloid bearing a succinimide moiety (3) were obtained from Isodon rubescens. Their structures and absolute configurations were determined by spectroscopy and quantum-chemical computational (13)C NMR and ECD data analysis. These alkaloids differ from known diterpene alkaloids and diterpenoids and are presumably biosynthesized from ent-kaurane diterpenoids.

Laxiflorol A (1), an unprecedented 7,8:15,16-di-seco-15-nor-21-homo-ent-kauranoid, and its precursor analogue, laxiflorol B (2), were isolated from the leaves of Isodon eriocalyx var. laxiflora. The absolute configuration of 1 was determined by spectral methods and quantum chemical calculations. Compound 2 exhibited weak cytotoxicity.

Covering: February 2008 to May 2014. Previous review: Nat. Prod. Rep., 2008, 25, 871–891 Several significant advances in the field of phytochemistry were made between 2008 and 2014 because of the high level of interest in Schisandraceae triterpenoids. In addition to a dramatic increase in the number of newly identified triterpenoids, the first complete synthesis of a schinortriterpenoid was accomplished. There has also been substantial progress in investigations of biological activity and mechanism of action. In this update, we review more than 250 new triterpenoids and describe their structures, classifications, biogenetic pathways, syntheses, and bioactivities.

Five 3,4-seco-cycloartane triterpenoids were isolated from the stems of Kadsura ananosma, two of which had rearranged 5/6 consecutive carbocycle rings C/D (trivially named ananosins A (1) and B (2)), one had a migrated CH3-18 (named ananosins C (3)), and two were analogs, ananosins D (4) and E (5). Their structures were characterized by comprehensive spectroscopic analysis, especially using 2D NMR spectra. A biogenetic pathway to 1 was proposed. These 5 compounds, together with 5 known analogs isolated from the same origin, were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549, PANC-1, and SK-BR-3 human cancer cells, but were inactive.

Five new biphenyls, tababiphenyls A-E (1-5), together with five known ones (5-10), were isolated from the leaves of Nicotiana tabacum, of which compound 1 possessed a seldom reported 6-carbons unit in biphenyls. Their structures were established on the basis of extensive spectroscopic analyses. All compounds were tested for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 3 and 5 exhibited high anti-TMV activities with inhibition rate of 48.4% and 32.1%, respectively, which were higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 18.6-28.7%, respectively. (C) 2014 Elsevier B.V. All rights reserved.

Thirteen new heterodimeric ent-kauranoids, bistenuifolins A-M (1-13), were isolated from the aerial parts of Isodon tenuifolius. The constituent units of compounds 1-6 were linked by a six-membered dihydropyran ring, while those of compounds 7-11 were joined by a rare single carbon-carbon bond (C-16→C-17'). The constituent units of 12 and 13 were linked via an unusual cyclobutane moiety. The structures of these metabolites were established via spectrometric analyses, and the absolute configurations of 1 and 4 were defined by single-crystal X-ray diffraction. Selected compounds were evaluated for their cytotoxicity against a small panel of human tumor cell lines; bistenuifolin B (2) exhibited weak inhibitory effects.

Twenty nine 6,7-seco-ent-kaurane-type diterpenoids including 18 new ones, laxiflorolides C-T (1-18), along with 21 known ones were obtained from Isodon eriocalyx var. laxiflora. Laxiflorolides E-G (3-5) are the first identified naturally occurring 6,7-seco-ent-kauranoids that feature a 3,6-epoxy unit, and laxi-florolide M (11) is the first identified naturally occurring 6-nor-6,7-seco-ent-kauranoid. The absolute configurations of compounds 1, 3, 6, and 11 were determined by single-crystal X-ray diffraction analyses. The cytotoxic activity of the isolates was evaluated by an MTF assay. (C) 2014 Elsevier Ltd. All rights reserved.

Three new phenolic amides, tabamides A-C (1-3), together with three known phenolic amides (4-6), were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-6 were also tested for their anti-tobacco mosaic virus (anti-TMV) activity. The results showed that compound 1 exhibited high anti-TMV activity with inhibition rate of 38.6%, which is higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 15.3-26.5%, respectively. (C) 2014 Published by Elsevier B.V. on behalf of Phytochemical Society of Europe.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is generally resistant to chemotherapy. In the present study, the cytotoxic activity of Rabdocoestin B (Rabd-B) against ESCC and the underlying mechanisms were investigated. The inhibitory effect of Rabd-B on KYSE30 and KYSE450 was evaluated by Cell Counting Kit-8 (CCK8) and colony formation assays in vitro. The cell cycle distribution and apoptosis of cells treated with Rabd-B were determined by flow cytometry. The mechanisms underlying the effects of Rabd-B were systematically examined by Western blot. The in vivo anti-tumor ability of Rabd-B was measured in mouse xenograft models and cisplatin (DDP) was used as positive control. Rabd-B efficiently induced G2/M phase arrest in ESCC cells by upregulating the Chk1/Chk2-Cdc25C axis to inhibit the G2→M transition facilitated by Cdc2/Cyclin B1. Furthermore, Rabd-B suppressed ATM/ATR phosphorylation, thereby inhibiting BRCA1-mediated DNA repair, which resulted in mitotic catastrophe and induced cell apoptosis. Rabd-B also decreased the activity of the Akt and NF-κB survival signaling pathways and ultimately initiated the caspase-9-dependent intrinsic apoptotic pathway in ESCC cells. The apoptosis induced by Rabd-B could be partially reversed by a caspase-9-specific inhibitor (Z-LEHD-FMK) and a pan-caspase inhibitor (Z-VAD-FMK). Moreover, Rabd-B effectively suppressed tumor growth in mouse xenografts which was comparable to that of DDP without significant injuries to the mice. Taken together, these findings indicate that Rabd-B is a promising precursor compound that may be useful as a treatment for ESCC and thus warrants further investigation.

Covering: December 2005 to June 2016. Previous review: Nat. Prod. Rep., 2006, 23, 673–698 Over the last decade, great efforts have been made to conduct phytochemistry research on the genus Isodon, which have led to the isolation and identification of a number of diterpenoids. At the same time, these newly reported diterpenoids with diverse structures have led to new findings on their biological functions and chemical synthesis research. In this update, we review more than 600 new diterpenoids, including their structures, classifications, biogenetic pathways, bioactivities, and chemical synthesis.

Fourteen new diterpenoids (1–14) based on four skeletal types and two known analogues (15 and 16) were isolated from the aerial parts of Isodon scoparius. Compound 2 is the first ent-kaurane diterpenoid featuring a 1,11-ether bridge, and the structures of these new compounds were established mainly by NMR and MS methods. The absolute configurations of 1 and 5 and the relative configuration of 3 were determined using single-crystal X-ray diffraction. The absolute configuration of 14 was determined by comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1, 4, and 15 were active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and they also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 1.0, 3.1, and 1.8 μM, respectively.

Seven previously undescribed 7,20-epoxy-ent-kaurane diterpenoids, isojiangrubesins A–G, along with seventeen known ones, were isolated from the aerial parts of Isodon rubescens. Their structures were characterized on the basis of spectroscopic methods and signal-crystal X-ray diffraction. All of these compounds were evaluated for their in vitro cytotoxicity against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). Four isolates exhibited significant inhibitory ability against all cell lines, with IC50 values ranging from 0.5 to 6.5 μM; They also strongly inhibited NO production in LPS-stimulated RAW264.7 cells.

Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis-dependent breast tumor growth. In the present study, the effects of EriB on human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB-231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo. We found that EriB was able to induce apoptosis accompanied by the activation of autophagy, which was evidenced by the increased accumulation of autophagosomes, acidic vesicular organelles formation, the microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) conversion from LC3B-I and p62 degradation. Meanwhile, EriB treatment time-dependently decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), leading to the inhibition of Akt/mTOR/p70S6K signaling pathway. Moreover, the blockage of autophagy obviously sensitized EriB-induced cell death, which suggested the cytoprotective function of autophagy in both MCF-7 and MDA-MB-231 cells. Interestingly, the autophagic features and apoptosis induction were prevented by reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine, indicating that ROS played an essential role in the mediation of EriB-induced cell death. Furthermore, in MDA-MB-231 xenograft model, EriB displayed a significant anti-tumor effect via the activation of autophagy and apoptosis in breast tumor cells. Taken together, our findings firstly demonstrated that EriB suppressed breast cancer cells growth both in vitro and in vivo, and thus could be developed as a promising anti-breast tumor agent.

Adenanthin has been recently shown to inhibit the enzymatic activities of peroxiredoxins (Prdx) land II through its functional alpha,beta-unsaturated ketone group serving as a Michael acceptor. A similar group is found in SK053, a compound recently developed by our group to target the thioredoxin-thioredoxin reductase (Trx-TrxR) system. This work provides evidence that next to Prdx I and II adenanthin targets additional proteins including thioredoxin-thioredoxin reductase system as well as protein disulfide isomerase (PDI) that contain a characteristic structural motif, referred to as a thioredoxin fold. Adenanthin inhibits the activity of Trx-TR system and PDI in vitro in the insulin reduction assay and decreases the activity of Trx in cultured cells. Moreover, we identified Trx-1 as an adenanthin binding protein in cells incubated with biotinylated adenanthin as an affinity probe. The results of our studies indicate that adenanthin is a mechanism-selective, rather than an enzyme-specific inhibitor of enzymes containing readily accessible, nucleophilic cysteines. This observation might be of importance in considering potential therapeutic applications of adenanthin to include a range of diseases, where aberrant activity of Prdx, Trx-TrxR and PDI is involved in their pathogenesis. (C) 2014 Elsevier Inc. All rights reserved.

Constitutively active Wnt signaling frequently occurs in most colon cancers. Therefore, inhibitors of Wnt signaling pathway could provide rational therapeutic effects for colorectal malignancy. Within this paper, we identified two inhibitors of Wnt signaling pathway, rabdoternin B and maoecrystal I from a natural ent-kauranoid library by a dual-luciferase reporter gene assay. The two compounds inhibited Wnt signaling pathway in a concentration-dependent manner and exhibited selective cytotoxicity toward a number of colon carcinoma cell lines SW480, HCT116, and HT29, with only weak cytotoxicity towards the normal colonic epithelial cell line CCD-841-CoN. Rabdoternin B and maoecrystal I treatment induced G2/M phase arrest efficiently in SW480 cells as revealed by flow cytometry analysis. A further study found that maoecrystal I decreased the expression of Wnt signaling target genes, including c-myc, cyclin D1, survivin and Axin2 in colon cancer cells. Collectively our data suggests that rabdoternin B and maoecrystal I are novel inhibitors of canonical Wnt signaling pathway and may possess potentials for colon cancer therapy.

Phytochemical investigation of EtOAc extracts of the aerial parts of Isodon wikstroemioides afforded 18 new ent-kaurane diterpenoids (wikstroemioidins E-V, 1-18), along with 17 known analogues (19-35). The absolute configurations of 1 and 16 were confirmed by single-crystal X-ray diffraction analysis. The isolates were screened against five human tumor cell lines; compounds 3, 4, 9, 11-13, 23, 25-28, and 33 exhibited significant cytotoxic activity against all five, with IC50 values ranging from 0.4 to 5.1 μM. In addition, 17 of the isolates strongly inhibited nitric oxide production in LPS-activated RAW264.7 macrophages.

One new 6,7-seco-ent-kaurane diterpenoid, sculponin T (1), was isolated from the aerial parts of Isodon sculponeatus, along with four known analogs, sculponeatin J (2), sculponeatin K (3), sculponeatin C (4), and sculponeatin Q (5). Their structures were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. Significant cytotoxic activity was observed for compound 2 against five human tumor cell lines with IC50 values ranging from 1.8 mu mol/L to 3.31 mu mol/L, and it also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 value of 3.3 mu mol/L. (C) 2014 Jian-Xin Pu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Phytochemical investigation of the aerial parts of Isodon sculponeatus afforded six new 7,20-epoxy-ent-kauranoids, sculponins U-Z (1-6), and 11 known diterpenoids (7-17). The structures of these new compounds were elucidated primarily by means of extensive spectroscopic analysis, and the absolute configuration of 1 was determined by single crystal X-ray diffraction. Compound 5 exhibited weak cytotoxic activity against HL-60, SMMC-7721, MCF-7, and SW-480 cell lines, and it also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 value of 13.8 μM.

Fourteen new rearranged 6/6/5/6-fused triterpenoid acids, namely, kadcoccine acids A–N (1–14), were isolated from an EtOAc-soluble extract of the stems of Kadsura coccinea. Their structures were characterized mainly by analyzing 1D and 2D NMR and HRESIMS data and were shown to feature a rare 14(13→12)-abeo-lanostane skeleton. Compounds 7 and 8 represented the first examples of a 5-substituted 2(5H)-furanone motif on the C-17 side chain of this skeleton. The absolute configurations of C-23 for compounds 1, 7, and 8 were determined by comparison of their experimental electronic circular dichroism spectra. All the isolates were screened for their in vitro cytotoxicity against six human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW-480, and HeLa), and compounds 2 and 8 exhibited weak inhibitory effects with IC50 values ranging from 3.11 to 7.77 μM.

Kadcoccinin A (1), a cage-like sesquiterpenoid possessing a tricyclo[4.4.0.03,10]decane scaffold, and the biosynthetically related kadcoccinin B (2) were isolated from the stems of Kadsura coccinea. Their structures and absolute configurations were determined from extensive spectroscopic analysis and quantum chemical calculations. Additionally, their cytotoxic and antifungal effects were initially evaluated, and a plausible biosynthetic pathway was proposed.

Fourteen enmein-type 6,7-seco-ent-kaurane diterpenoids, seven new ones (sculponins M-S, 1-7) and seven known compounds (8-14), were isolated from the aerial parts of Isodon sculponeatus. Compound 1 is the first example of an ent-kauranoid, possessing a 11,12-epoxy group, and compounds 6 and 7 have a rare 3,6-epoxy group. The structures were established primarily by NMR and MS methods, and the absolute configurations of 1, 3, and 6 were determined by single-crystal X-ray diffraction. Compound 14 showed significant cytotoxic activity against five human tumor lines, with IC50 values ranging from 1.0 to 3.5 mu M, and it also inhibited NO production in LPS-stimulated RAW264.7 cells, with an IC50 value of 2.2 mu M.

Scopariusic acid (1), a new ent-clerodane-based meroditerpenoid with a unique cyclobutane ring and an unusual 1-octen-3-ol substituent, together with its biosynthetic related compound 2, were isolated from the aerial parts of Isodon scoparius. The structures of 1 and 2, including their absolute configurations, were determined by spectroscopic methods, single-crystal X-ray diffraction analysis, and chemical methods. Compound 1 showed weak cytotoxicity and moderate immunosuppressive activity.