Phenolic acid glycosides from Parmentiera cereifera Seem. (Candle tree)

Two new phenolic acid glycosides, parmentins A (1) and B (2) were isolated from the methanolic extract of the leaves and stems of candle tree (Parmentiera cereifera Seem). These compounds were accompanied by a mixture of β-sitosterol and stigmasterol (3), β-sitosterol glucoside (4), isovanillic acid (5), vanillic acid (6), and p-hydroxybenzoic acid (7). The structures of the isolated compounds were determined on the basis of physical and spectroscopic analyses, including 1D and 2D NMR (¹H, ¹³C, COSY, HSQC and HMBC) and mass spectrometry (HR-ESI-MS).     

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC₅₀?=?0.67?±?0.09?µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.     

Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities

Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were mainly determined by analysis of NMR and MS data, along with chemical methods. Preliminary screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells showed that compounds 1, 2, and 5 inhibited the production of nitric oxide (NO) with IC₅₀ values of 37.8, 7.1, and 42.5 μM, respectively. Compound 2 also inhibited NO production in LPS-stimulated RAW264.7 murine macrophages with an IC₅₀ value of 27.0 μM. Moreover, these inhibitory effects correlated with the suppressive effect of compound 2 on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 and BV2 cells. In addition, compounds 2 and 5 significantly inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with the same IC₅₀ value (8.2 μM).     

Identification of caffeoylquinic acid derivatives as natural protein tyrosine phosphatase 1B inhibitors from Artemisia princeps

Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1–10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC₅₀ 11.1?μM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development.     

Two new monoterpenes and one dicaffeic acid ester from Sibiraea angustata with hypolipidemic activities in HepG2 cells in Vitro

Two new monoterpenes, named sibiscolacton B (1) and sibiscolacton C (2), together with a sorbate obtained from the natural product 1, 6-sorbitol-O-dicaffeic acid ester (3), were isolated from an aqueous extract of the aerial portion of Sibiraea angustata. The compounds’ structures were elucidated on the basis of extensive spectroscopic analysis, as well as literature comparisons. A preliminary in vitro bioassay showed that all of the compounds exhibited hypolipidemic effects in HepG2 cells.     

Diterpenoids from the needles and twigs of the cultivated endangered pine Pinus kwangtungensis and their PTP1B inhibitory effects

Pinus kwangtungensis is an endangered pine species native to China. In the present study, 15 diterpenoids including three new labdane-type analogs were isolated and characterized during a pioneer phytochemical investigation on a mass-limited sample of the needles and twigs of this plant, which is growing in a Cantonese garden. The new structures, (4S,5R,9S,10R)-6-oxo-labd-7,13-dien-16,15- olid-19-oic acid (1), 15(S)-n-butoxypinusolidic acid (2), and β-d-glucopyranosyl- (4S,5R,9S,10R)-labda-8(17),13-dien-15,16-olid-19-oate (3), were established by extensive spectroscopic methods and some chemical transformations. Among the isolates, lambertianic acid (10) and cassipourol (15) showed inhibitory activities against human protein tyrosine phosphatase 1 B (PTP1B), a target for the treatment of type-II diabetes and obesity, with IC₅₀ values of 25.5 and 11.2 μM, respectively.     

New cytotoxic protolimonoids from the stem bark of Aglaia argentea (Meliaceae)

Two new protolimonoid compounds, namely, argentinin A (1) and B (2) along with five known triterpenoid compounds, dammar-24-en-3α-ol (3), 3-epi-cabraleahydroxy lactone (4), (E)-25-hydroperoxydammar-23-en-3β,20-diol (5), mixture of eichlerianic acid and shoreic acid (6a and 6b), and dammar-24-en-3α,20-diol (7), were isolated from the stem bark of Aglaia argentea. The structure of new compounds were elucidated by spectroscopic methods including one and two-dimensional NMR as well as high-resolution mass spectrometric analysis. All of the compounds were tested for their cytotoxic effects against P-388 murine leukemia cells in vitro. Among those isolated compounds, argentinin A (1) showed the strongest activity with an IC₅₀ value of 1.27 μg/mL (3.05 μM).     

Anti-inflammatory activity of constituents from Glechoma hederacea var. longituba

Rosmarinic acid, its analogues, and a phenolic compound were obtained from G. hederacea var. longituba. There were two new compounds, methyl isoferuloyl-7-(3,4-dihydroxyphenyl) lactate (1) and benzyl-4′-hydroxy-benzoyl-3′-O-β-d-glucopyranoside (4), and four known compounds (2, 3, 5 and 6). The structures of these compounds were determined on the basis of spectroscopic methods. Each compound was tested by NF-κB luciferase assay and three rosmarinic acid analogues inhibited NF-κB production and the induction of COX-2 and iNOS mRNA in HepG2 cells.     

Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines

Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K_i = 5.9 nM; 11d: K_i = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K_i = 5.9 nM; 11c: K_i = 6.0; 12c: K_i = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ₂ affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ₁ and σ₂ receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5–2-fold) as well as for bromo derivative 18c (≈3-fold).     

Inhibitory effects of N-(acryloyl)benzamide derivatives on tyrosinase and melanogenesis

Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N-(acryloyl)benzamide) derivatives (1a–1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ± 2.14% inhibition) and 1j (25.99 ± 2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ± 2.93% inhibition), and docking studies indicated 1a (−6.9 kcal/mole) and 1j (−7.5 kcal/mole) had stronger binding affinities for tyrosinase than kojic acid (−5.7 kcal/mole). At a concentration of 25 μM, 1a and 1j were nontoxic in B16F10 melanoma cells and exhibited stronger tyrosinase inhibition (59.70% and 76.77%, respectively) than kojic acid (50.30% inhibition) or arbutin (41.78% inhibition at 400 μM). Similarly, in B16F10 melanoma cells, compounds 1a and 1j at 25 μM decreased total melanin content by 47.97% and 61.77%, respectively (kojic acid; 38.98%). Similarities between inhibitions of tyrosinase activity and melanin contents suggested the anti-melanogenic effects of 1a and 1j were due to tyrosinase inhibition. The excellent DPPH scavenging activity of 1j suggests it might enhance in vivo effect on melanin contents. The study suggests compound 1j offers a potential starting point for the development of safe, potent tyrosinase inhibitors.     

Monoterpenoids and Triterpenoids from Pterocephalus hookeri with NF-κB inhibitory activity

In this study, we isolated two new monoterpenoids hookerinoids A and B (1 and 2; rare arranged nonglycosidic bis-iridoids) and hookerinoid C (3; a novel norursane-type triterpenoid) in addition to two known compounds, 11,12-epoxy-2,6-dihydroxy-24-norursa-1,4-dien-3-on-2-on-(28 → 13)-olide (4) and rivularicin (5), from Pterocephalus hookeri. The structures of 1–3 were established using one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionisation mass spectrometry. All compounds were isolated from this plant for the first time. Bis-iridoids isolated from P. hookeri possessed secoiridoid/iridoid subtype skeletons. Therefore, bis-iridoids can be considered chemotaxonomic markers of P. hookeri. The origins of the new compounds (1–3) were postulated and their inhibitory activities on a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway were assayed; 1 and 2 showed obvious activity in inhibiting NF-κB.     

Two new flavonol glycosides from the leaves of Cleome viscosa L.

From the leaves of Cleome viscosa L., two new flavonol glycosides, named visconoside A (1) and visconoside B (2), together with six known flavonol glycosides, vincetoxicoside A (3), vincetoxicoside B (4), kaempferitrin (5), kaempferide 3-O-β-d-glucopyranoside 7-O-α-l-rhamnopyranoside (6), kaempferol 3-O-β-d-glucopyranoside 7-O-α-l-rhamnopyranoside (7), and isorhamnetin 3-O-β-d-glucopyranoside (8) were isolated by various chromatography methods. Its chemical structure was elucidated by IR, UV, HR-ESI-MS, NMR 1D and 2D experiments and compared with literatures.     

Bioactive triterpene glycosides from the fruit of Stauntonia hexaphylla and insights into the molecular mechanism of its inflammatory effects

Chromatography of the ethanol extract of the medicinal fruit Stauntonia hexaphylla resulted in the purification of 26 compounds (1–26), including two undescribed triterpene saponins 1 and 2 (hexaphylosides A and B). Their structures were confirmed by spectroscopic data, including IR, HR QTOF MS, ¹H, ¹³C NMR, COSY, HMQC, HMBC, and TOCSY, and HPLC sugar analysis after acid hydrolysis. The anti-inflammatory effects of the high-purity constituents (1–26) on lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells were investigated by screening nitric oxide production. The NO inhibitory activity of compounds 6 and 10 with the IC₅₀ values of 1.33 and 1.10 µM, respectively. The structure-activity relationships (SAR) of the isolated compounds were also analyzed. Furthermore, compounds 6 and 10 inhibited the protein expression inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 via Western blotting analysis. This showed that compounds 6 and 10 contributed to the anti-inflammatory effects of S. hexaphylla fruit, which could be developed as a natural nutraceutical and functional food ingredient.     

Eudesmanolide sesquiterpenes and protein tyrosine phosphatase 1B inhibitory ent-kaurene diterpenes from aerial parts of Indonesian Wedelia prostata

Seven eudesmanolide sesquiterpenes (1–7) and two ent-kaurene diterpenes (8 and 9) including two new (9R)-eudesman-9,12-olides, named wedelolides I and J (1 and 2), were isolated from the aerial parts of Indonesian Wedelia prostata. The structures of 1 and 2 were assigned based on their spectroscopic data. Diterpenes 8 and 9 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC₅₀ values of 8.3 and 28 μM, respectively. Among sesquiterpenes 1–7, compound 4, wedelolide D, exhibited 32% inhibitory activity against PTP1B at 20 μM.     

Two new saponins from Paronychia capitata

Two new oleanane-type triterpene glycosides, 3˗O˗β˗D˗glucopyranosyl˗28˗O˗[β˗D˗glucopyranosyl˗(1→2)˗β˗D˗xylopyranosyl˗(1→6)˗β˗D˗glucopyranosyl]medicagenic acid (1) and 3˗O˗β˗D˗glucopyranosyl˗28˗O˗[β˗D˗glucopyranosyl˗(1→6)˗β˗D˗glucopyranosyl˗(1→2)˗ β˗D˗xylopyranosyl]oleanolic acid (2), named capitatosides A and B respectively, were isolated from the butanol extract of Paronychia capitata (L.) Lam., along with seven known compounds. The structures of the isolated compounds were established by spectroscopic methods, mainly HRMS, 1D and 2D NMR (¹H, ¹³C, COSY, HSQC, HMBC and NOESY) techniques, whereas those of the known compounds were identified by spectral comparison with reported literature data.     

Novel γ-lactone derivatives from Trigonostemon heterophyllus with their potential antiproliferative activities

Two novel γ-lactone derivatives, trigoheterophines A (1) and B (2), together with four known furan derivatives (3–6), were isolated from the stems and leaves of Trigonostemon heterophyllus. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A (1) and B (2) represent an unusual type of γ-lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds (3–6) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–6 showed significant antiproliferative effects against various human cancer cell lines with IC₅₀ values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ-lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents.     

Caged xanthones displaying protein tyrosine phosphatase 1B (PTP1B) inhibition from Cratoxylum cochinchinense

Four new caged xanthones (1–4) and two known compounds (5, 6) were isolated from the roots of Cratoxylum cochinchinense, a polyphenol rich plant, collected in China. The structures of the isolated compounds (1–6) were characterized by obtaining their detailed spectroscopic data. In particular, compounds 1 and 6 were fully identified by X-ray crystallographic data. The isolated compounds (1–6) were evaluated against protein tyrosine phosphatase 1B (PTP1B), which plays an important role in diabetes, obesity, and cancer. Among these compounds, 3, 4, and 6 displayed significant inhibition with IC₅₀ values of 76.3, 43.2, and 6.6 µM, respectively. A detailed kinetic study was conducted by determining K_m, V_max, and the ratio of K_ik and K_iv, which revealed that all the compounds behaved as competitive inhibitors.     

Three new iridoid glycosides isolated from the traditional herb Siphonostegia chinensis with NF-κB inhibitory activity

Siphonoids A–C (1–3), among which siphonoids A-B (1–2) are rare (E)-p-coumaroyl iridoids, were isolated from Siphonostegia chinensis along with ten known iridoids (4–13) and four lignans (14–17). The structures of the compounds were established by 1D- and 2D-NMR spectroscopy and mass spectrometry. Most of the iridoids isolated from S. chinensis were found to possess (E)-p-coumaroyl iridoid subtype skeletons. Hence, this type of iridoid could be regarded as a chemotaxonomic marker of S. chinensis. The inhibition activities for the NF-κB pathway of iridoids (1–6) were detected. The present results showed that compounds 1–2 and 4–6 processed moderate activity towards the inhibition of NF-κB.     

Antioxidant,anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives

During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-β-phenyl-α,β-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a–1n and one (Z)-2,3-DPA-derivative 1l′ using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ± 3.53%, IC₅₀ = 20.04 ± 1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ± 2.93%, IC₅₀ = 30.64 ± 1.27 μM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (−7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (−5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 μM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 μM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.