Cytotoxic abietane-type diterpenoids from twigs and leaves of Croton laevigatus

Seven new abietane-type diterpenoids, crotolaevigatones A–G (1–7), one new aromatic compound, hexyl Z-ferulate (8), along with three known diterpenoids (9–11) and one known aromatic ester, hexyl E-ferulate (12), were obtained from the twigs and leaves of Croton laevigatus. The structures of all isolated compounds were established on the basis of extensive NMR and MS spectroscopic analyses. Compounds 2 and 7 exhibited weak anti-proliferative activity against the A549 and MDA-MB-231 cancer cells, while compound 10 selectively showed significant inhibitory activity against the A549 cancer cells.     

Phytochemistry and antiglycation activity of Aloe sinkatana Reynolds

A new anthraquinone along with 10 known compounds were isolated from the leaves of Aloe sinkatana Reynolds (Aloaceae), and their structures were elucidated as the new compound 2,8-dihydroxy-6-(hydroxymethyl)-1-methoxyanthracene-9,10-dione (1) and the known compounds Aloe-emodin (2), feralolide (3), 1-hydroxy-5-methoxy-3-methyl-9,10 dihydroanthracene 9,10-dione (4), β-sitosterol (5), β-sitosterol with glycosidic bond (6), microdontin (7), homoaloins A (8) and B (9) and aloins A (10) and B (11). Characterization of compounds 1–9 was based on spectral analyses and comparison with reported data, particularly the new compound 1 was identified by 1D- and 2D NMR, mass spectroscopic and X-ray crystallography analyses. Antiglycation activity of the extracts and isolated compounds were carried out using the hemoglobin-δ-gluconolactone and glucose–bovine serum albumin assays. The results obtained showed that MeOH and EtOAc extracts as well as compound 1 showed an inhibitory effect on early stage protein glycation. Compound 1 also showed significant inhibitory effects against glucose-induced advanced glycation end-products.     

Chemical constituents from the pericarps of Zanthoxylum bungeanum and their chemotaxonomic significance

The phytochemical study of the pericarps of Zanthoxylum bungeanum Maxim under the guidance of bioactivity led to the isolation of 18 compounds, including a new isobutylhydroxyamide (1) and 17 known compounds, i.e. six alkylamides (2–7), five coumarins (8–12), one benzene derivative (13), three flavonoids (14–16), and two sterols (17–18). Their structures were elucidated based on extensive spectroscopic methods (HRESIMS, 1D and 2D NMR experiments) and by comparison with literature data. New compound (1) and known compound (2) are cis-trans isomeric isobutylhydroxyamides. Among them, compounds 9, 10, and 12 were isolated for the first time from Z. bungeanum, compound 11 was firstly recovered from the genus Zanthoxylum, and compound 14 was reported for the first time from the Rutaceae family. The chemotaxonomic significance of isolated compounds from Z. bungeanum is discussed.     

New unsaturated fatty acid and other chemical constituents from the roots of Cola rostrata K. Schum. (Malvaceae)

Phytochemical investigation of the roots of Cola rostrata K. Schum. led to the isolation of a new unsaturated fatty acid, named rostratanic acid (1), together with fourteen known compounds, lignoceric acid, friedelan (7), friedelanone (8), bauerenol (3), lupeol (4), herranone (9), acotatarone A (11), betulinic acid (6), betulin (5), nonanedioc acid (2), arjunolic acid (10) stigmasterol, β−sitosterol, and β−sitosterol-3-O-β-D-glucopyranoside. The structure of the new compound as well as those of the known compounds were established by means of spectroscopic methods: NMR analysis (¹H and ¹³C NMR, ¹H–¹H–COSY, HSQC and HMBC) and high-resolution mass spectrometry (HR-ESI-MS), and by comparison with previously reported data. Two of those known compounds were modified chemically to afford three new derivatives. All those compounds were tested for their cytotoxic activity against the human cervix carcinoma KB-3-1 cells and their antibacterial activity against Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa and Staphylococcus aureus. Although the crude extract gave weak antibacterial activity, none of the isolated compounds showed antibacterial activity, and, only the prenylated derivative showed weak cytotoxicity. In addition, the chemotaxonomic significance of the species Cola rostrata is discussed.     

Polyphenols from the bark of Rhus verniciflua and their biological evaluation on antitumor and anti-inflammatory activities

Bioassay-guided fractionation and chemical investigation of the extract of Rhus verniciflua bark resulted in the identification of six polyphenols, rhusopolyphenols A–F (1–6), together with four known compounds including (2R,3S,10S)-7,8,9,13-tetrahydroxy-2-(3,4-dihydroxyphenyl)-2,3-trans-3,4-cis-2,3,10-trihydrobenzopyrano[3,4-c]-2-benzopyran-1-one (7), peapolyphenol C (8), cilicione-b (9) and (αR)-α,3,4,2′,4′-pentahydroxydihydrochalcone (10). The structures of these polyphenols were elucidated by spectroscopic analysis, including 1D and 2D NMR, and HR-ESIMS, and their absolute configurations were further confirmed by a combination of chemical methods and CD data analysis. All isolates were evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15), and compounds 4–6, 9 and 10 showed antiproliferative activity against the tested cells, with IC₅₀ values of 3.31–18.51 μM. On the basis of the expanded understanding that inflammation is a crucial cause of tumor progression, the anti-inflammatory activities of these compounds were determined by measuring nitric oxide (NO) levels in the medium of murine microglia BV-2 cells. Compounds 5 and 10 significantly inhibited NO production in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells with IC₅₀ values of 28.90 and 12.70 μM, respectively.     

Nardonaphthalenones A and B from the roots and rhizomes of Nardostachys chinensis Batal.

Nardonaphthalenones A and B (1–2), one new apo-α-carotenone (3) and four new monoterpenoids (4, 8–9 and 11), along with six known compounds (5–7, 10, 12–13) were isolated from the dried roots and rhizomes of Nardostachys chinensis Batal. Their structures were elucidated by analysis of the spectroscopic data including NMR, HRESIMS and circular dichroism data. Furthermore, the serotonin transporter (SERT)-regulating activities of these isolates were evaluated, among them compound 3 showed the strongest enhancement activity while compound 12 showed a moderate inhibition activity on SERT.     

Inhibitory effects of p-dodecylaminophenol on the invasiveness of human fibrosarcoma cell line HT1080

Cancer is a major cause of death, and the development of new anticancer drugs is urgently needed. Invasion and metastasis are the primary causes of death due to cancer rather than growth of the primary tumor. In the current study, we examined the anti-invasive effects of p-dodecylaminophenol (1), which was developed based on N-(4-hydroxyphenyl)retinamide (2), a synthetic amide of all-trans-retinoic acid (3). In HT1080 cells 1 inhibited growth, induced apoptosis and arrested the cell cycle in S phase in a dose-dependent manner. In addition, 1 significantly suppressed cell invasion, and the activity and mRNA expression of matrix metalloproteinase-9 (MMP-9). Furthermore, the expression of the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is a negative regulator of MMP-9, was increased by treatment with 1. These results suggest that 1 could be an effective anti-cancer agent that suppresses cell growth through apoptosis induction and cell cycle arrest, which also inhibits cell invasion by decreasing MMP-9 expression due to an increase in RECK. Compound 1 might be useful clinically as a new and potent anticancer agent that could overcome adverse side effects of the retinoids.     

Design of antitumor agents containing carbohydrate based on GLUT1, and evaluation of antiproliferative activity

A series of novel carbohydrate-modified antitumor compounds were designed based on glucose transporter 1 (GLUT1), and evaluated for their anticancer activities against four cancer cell lines. The ribose derivatives (compound 9 and 10) exhibited modest inhibitory activity. The compound 9 significantly inhibited the migration of A549 cell and induced A549 cell apoptosis in a concentration-dependent manner. Moreover, compound 9 blocked A549 cells at the G0/G1 phase. The cellular uptake studies suggested that ribose-modified compound 9 could be taken through GLUT1 in A549 cell line.     

Alkaloids from the mangrove endophytic fungus Diaporthe phaseolorum SKS019

Six new alkaloids including four new chromeno[3,2-c]pyridines, diaporphasines A-D (1–4), and two new isoindolinones, meyeroguillines C and D (6–7), as well as three known compounds meyeroguilline A (5), 5-deoxybostrycoidin (8), and fusaristatin A (9), were isolated from an endophytic fungus Diaporthe phaseolorum SKS019. Their structures were determined by analysis of 1D and 2D NMR and mass spectroscopic data. Compounds 1–9 are alkaloid components reported for the first time from the Diaporthe sp., and diaporphasines A-D (1–4) are the third examples of alkaloids possessing the unique chromeno[3,2-c]pyridine nucleus. All isolated compounds 1–9 were evaluated for their cytotoxic activity in vitro using MDA-MB-435, HepG2, MCF10A, HCT116, and NCI-H460 human cell lines. Compound 8 exhibited cytotoxicity against MDA-MB-435 and NCI-H460 human cancer cell lines with IC₅₀ values of 5.32 and 6.57 μM, respectively, and compound 9 showed growth-inhibitory activity against MDA-MB-435 human cancer cell line with IC₅₀ value of 8.15 μM.     

Chemical constituents from Cistanche sinensis (Orobanchaceae)

Phytochemical investigation of 70% aqueous EtOH extract of Cistanche sinensis led to the isolation of fifteen compounds (1–15), including nine phenylethanoid glycosides (PhGs, 1–9), five iridoid glycosides (10–14), and one lignan glycoside (15). Their structures were determined on the basis of 1D- and 2D-NMR experiments and by comparison with physical data of known compounds. Among the isolated compounds, 1 was identified as a new compound, three compounds (9, 14, and 15) were firstly reported from the genus Cistanche, and seven compounds (2–6, 11, and 12) were isolated from C. sinensis for the first time. PhGs with a 6′-O-rhamnosyl moiety such as cistansinenside B (1), poliumoside (7), and 2′-O-acetylpoliumoside (9) could serve as chemotaxonomic markers to differentiate C. sinensis from other species of Cistanche.     

Hypolipidemic constituents from the aerial portion of Sibiraea angustata

Two new monoterpene acylglucosides (1–2) and one new aromatic glycoside (3), together with five known compounds (4–8), were isolated from 95% ethanol extract of Sibiraea angustata. The structures of these compounds were characterized by 2D-NMR and mass spectrometry. Compounds were evaluated for their hypolipidemic activity using oleic acid-induced lipid accumulation in HepG2 cells. RT-PCR analysis revealed that compound 5 could decrease the expression level of fatty acid synthase (FASN). Lipidomics analysis indicated that compound 5 significantly decreased the levels of 11 lipids in oleic acid-induced lipid accumulation, including triglycerides (TG), diglycerides (DG), phosphatidylcholines (PC) and 1-acyl-sn-glycero-3-phosphocholines (lysoPC). These data demonstrated that terpene acylglucosides are the major active constituents in Sibiraea angustata.     

Phytochemical investigation on the fruiting body of Russula aruea Pers

Phytochemical investigation of ethyl acetate fraction from Russula aruea Pers fruiting body led to the isolation and identification of one new isolactarane sesquiterpene (1) and 11 known compounds, including four sesquiterpenes (2-5), four sterols (6–9), one allitol (10), and two fatty acids (11–12). The structure of compound 1 was elucidated by means of spectroscopic analysis, including 1D and 2D NMR, HR-ESI-MS, and X-Ray experiments. Compounds 1–3 and 5–12 are herein reported for the first time from Russula genus, while compound 4 is firstly described in R. aruea. The sesquiterpenes in R. aruea could serve as chemotaxonomic markers.     

Chemical constituents from Sophora tonkinensis and their glucose transporter 4 translocation activities

Bioassay-guided phytochemical investigation of the EtOAc fraction (ST-EtOAc) from the roots of Sophora tonkinensis resulted in the isolation of a new compound 6aR,11aR-1-hydroxy-4-isoprenyl-maackiain (1), along with 12 known compounds (2–13). The structure of the new compound was established by 1D and 2D NMR, MS data and circular dichroism analysis. Polyprenylated flavonoids 6–9 and 11–13 increased GLUT-4 translocation by the range of 1.35–2.75 folds. Sophoranone (8) exerted the strongest activity with 2.75 folds GLUT-4 translocation enhancement at the concentration of 10 μM. This is the first report of the GLUT-4 translocation activity of the plant Sophora tonkinensis.     

Vernoguinamide: A new ceramide and other compounds from the root of Vernonia guineensis Benth. and their chemophenetic significance

The chemical investigation of the roots of Vernonia guineensis Benth. (Asteraceae) resulted in the isolation of a new ceramide, named vernoguinamide (1), together with fifteen known compounds, including three anthraquinones, physion (2), erythroglaucin (3) and emodin (4), three triterpenoids, hop-17(21)-en-3β-yl acetate (5), lupeol (6) and betulinic acid (7), six steroids, vernoguinoside A (8), vernoguinoside (9), β-sitosterol 3-O-β-D-glucoside (10), stigmasterol 3-O-β-D-glucoside (11), stigmasterol (12) and β-sitosterol (13) and three fatty acid derivatives, tetracosanoic acid (14), tricosanic acid (15) and arachidic acid glycerol ester (16). The structure of the new compound as well as those of the known compounds were established by spectrometric analysis including HRESI-MS, 1D and 2D-NMR and by comparison with the previously reported data. Among these compounds, the anthraquinones 2–4 and the triterpene 5 were isolated for the first time from Vernonia genus and compounds 6, 7 and 14–16 were extracted for the first time from the species. The isolated compounds were tested for their antibacterial activity and 3, 8 and 9 were the most active compounds against the tested bacteria. Furthermore, the chemophenetic relationships of the isolated compounds and their significance were also discussed.     

(−)-9′-O-(α-l-Rhamnopyranosyl)lyoniresinol from Lespedeza cuneata suppresses ovarian cancer cell proliferation through induction of apoptosis

Lespedeza cuneata (Dum. Cours.) G. Don. (Fabaceae), known as Chinese bushclover or sericea lespedeza, has been used in traditional medicine to treat diabetes, hematuria, and insomnia, and it has been reported that bioactive compounds from L. cuneata possess various pharmacological properties. However, there has been no study to determine the active compounds from L. cuneata with potential activity against ovarian cancer. This study aimed to isolate cytotoxic compounds from L. cuneata and identify the molecular mechanisms underlying the apoptosis pathway in ovarian cancer cells. Based on cytotoxic activity identified in the screening test, chemical investigation of the active fraction of L. cuneata led to the isolation of nine compounds including four lignanosides (1–4), three flavonoid glycosides (5–7), and two phenolics (8–9). Cytotoxicity and the molecular mechanism were examined by methyl thiazolyl tetrazolium (MTT) assay and Western blot analysis. Of the isolated compounds, (?)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol (3) demonstrated the strongest effect in suppressing A2780 human ovarian carcinoma cell proliferation in a dose-dependent manner, with an IC₅₀ value of 35.40?±?2.78?μM. Control A2780 cells had normal morphology, whereas cell blebbing, shrinkage, and condensation were observed after treatment with compound 3. Western blotting analysis showed that compound 3 inhibited A2780 human ovarian cancer cell viability by activating caspase-8, caspase-3, and PARP, which contributed to apoptotic cell death. These results suggest that (?)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol (3) has potent anticancer activities against A2780 human ovarian carcinoma cells through the extrinsic apoptotic pathway. Therefore, (?)-9′-O-(α-l-rhamnopyranosyl)lyoniresinol is an excellent candidate for the development of novel chemotherapeutics.     

α-Glucosidase inhibitory constituents from Chrozophora plicata

Five new secondary metabolites have been isolated from Chrozophora plicata including an acacetin derivative (1), three pyrrole alkaloids plicatanins A–C (2–4, resp.) and the bilactone plicatanone (5). Together with these compounds, the known compounds, β-sitosterol (6), methyl p-coumarate (7), 4-hydroxyphenylacetic acid (8), succinic acid (9), speranberculatine A (10), β-sitosterol-3-O-β-d-glucopyranoside (11) and apigenin-5-O-β-d-glucopyranoside (12) have also been isolated. The structures of isolates 1–12 were established by 1D (¹H, ¹³C) and 2D NMR (HMQC, HMBC, COSY) spectroscopy and mass spectrometry (EIMS, HREIMS, FABMS, HRFABMS). The structure of plicatanin A (3) was further confirmed through single crystal X-ray technique. Compounds 1–12 were evaluated for their inhibitory activity against the enzyme yeast α-glucosidase. The compound 4 was found to be most potent with IC₅₀ value 27.8 μM.     

Lignan derivatives from Selaginella tamariscina and their nitric oxide inhibitory effects in LPS-stimulated RAW 264.7 cells

The chemical characterization of Selaginella tamariscina leaves resulted in the isolation of five lignanoside derivatives (1–4 and 6) and one neolignan (5). These compounds include three new lignanosides, tamariscinosides D–F (1–3), and one liriodendrin (4) that were isolated for the first time from this plant, together with two known compounds, (2R,3S)-dihydro-2-(3,5-dimethoxy-4-hydroxyphenyl)-7-methoxy-5-acetyl-benzofuran (5) and moellenoside B (6). The chemical structures of these isolated compounds were determined using 1D and 2D NMR, MS, and CD spectroscopic data, and the results were compared to data previously reported in the literatures. These compounds were also evaluated in terms of their inhibition of NO production in lipopolysaccharide (LPS)-stimulated activity in the macrophage cell line RAW 264.7. Among them, compounds 1, 2, 5, and 6 exhibited a significant inhibition with IC₅₀ values ranging from 32.3 to 55.8 μM.     

11a-N-tosyl-5-carbapterocarpans: Synthesis,antineoplastic evaluation and in silico prediction of ADMETox properties

11a-N-tosyl-5-carbapterocarpans (5a–c and 6a–c), 9-N-tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (7), 11a-N-tosyl-5-carbapterocarpen (8) analogues of LQB-223 (4a), were synthesized through palladium catalyzed azaarylation of substituted dihydronaphtalenes (14a–c) and cyclohexadiene (15), respectively, with N-tosyl-o-iodoaniline (11). In order to understand the role of the N-tosyl moiety for the pharmacological activity, the azacarbapterocarpen (9) was also synthesized by Fischer indol reaction. The structural requirements at the A and D-rings for the antineoplastic activity toward human leukemias and breast cancer cells were evaluated as well. Substitutions on the A-ring of 4a and analogues alter the effect on different breast cancer subtypes. On the other hand, A-ring is not essential for antileukemic activity since compound 7, which does not contain the A-ring, showed efficacy with high selectivity indices for drug-resistant leukemias. On the other hand, substitutions on the D-ring of 4a for fluorine or iodine did not improve the antileukemic activity. In silico studies concerning Lipinskís rule of five, ADMET properties and drug scores of those compounds were performed, indicating good physicochemical properties for all compounds, in special for compound 7.     

A new phenolic acid from Zanthoxylum nitidum var. tomentosum (Rutaceae) and its chemotaxonomic significance

A new compound, nitomentosin (1), along with sixteen known compounds (2–17), were isolated from Zanthoxylum nitidum var. tomentosum (Rutaceae). The structure of compound 1 including absolute configurations was determined by detailed spectroscopic information (HRESIMS and NMR) and from the electronic circular dichroism (ECD) spectra. From the present investigation, compound 3 is a new natural compound although it has been reported previously as a synthetic substance, and compound 15 is found for the first time in a plant. All these compounds except 2, 5–10 and 12 were isolated from Z. nitidum for the first time. Furthermore, the chemotaxonomic significance of the isolated compounds is discussed.     

New tirucallane triterpenoids from Picrasma quassioides with their potential antiproliferative activities on hepatoma cells

Seven new tirucallane-type triterpenoids (1–7), kumuquassin A-G, along with 20 known analogues (8–27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ^{17, 20} double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.