New butenolide derivatives from the marine sponge-derived fungus Aspergillus terreus

Two new butenolide derivatives (±)-asperteretal D ((±)-1) and asperteretal E (2) containing rare 2-benzyl-3-phenyl substituted lactone core, together with nine known analogues (3–11) were obtained from a fungus Aspergillus terreus derived from the marine sponge Phakellia fusca. All the structures were elucidated on the basis of extensive NMR spectroscopic data. The chiral chromatography analyses allowed the separation of the (±)-asperteretal D, of which the absolute configurations were determined by comparing the experimental to calculated electronic circular dichroic (ECD) spectra. Compounds (±)-1, 2–5, and 7 exhibited potent inhibitory activities against α-glucosidase with IC₅₀ values ranging from 8.65 to 20.3?µM (positive control acarbose with an IC₅₀ value of 320?µM). In addition, derivatives 5–8 also showed moderate antioxidant activities.     

Six new dammarane-type triterpene saponins from the processed leaves of Panax notoginseng

Six new dammarane-type triterpenoid saponins, notoginsenosides SFt₅–SFt₁₀ (1–6) were isolated from the processed leaves of Panax notoginseng (Burk.) F.H.Chen (Araliaceae), together with eight known notoginsenosides (7–14), fourteen known ginsenosides (15−28), two known vinaginsenosides (29−30), and one known gypenoside (31). Their structures were established by detailed spectroscopic analysis (NMR, UV, IR, HRESI-MS) and acidic hydrolysis. Four compounds notoginsenoside SFt₁ (7), ginsenosides Rg₅ (17), C-Mc (23) and 20(R)–Rg₃ (25) have significant protective effects against L-glutamate-induced SH–SY5Y nerve injury (10 μM).     

Tyrosinase inhibitory study of flavonolignans from the seeds of Silybum marianum (Milk thistle)

Anti-melanogenesis effects of silymarin from milk thistle have been reported recently, but detailed tyrosinase inhibition properties of individual components have not been investigated. This study purported to substantiate tyrosinase inhibition and its mechanism based on a single metabolite. The responsible components for tyrosinase inhibition of target source were found out as flavonolignans which consist of isosilybin A (1), isosilybin B (2), silydianin (3), 2,3-dihydrosilychristin (4), silychristin A (5), silychristin B (6) and silybin (7), respectively. The isolated flavonolignans (1–7) inhibited both monophenolase (IC₅₀ = 1.7–7.6 µM) and diphenolase (IC₅₀ = 12.1–44.9 µM) of tyrosinase significantly. Their inhibitions were 10-fold effective in comparison with their mother skeletons (8–10). Inhibitory functions were also proved by HPLC analysis using N-acetyl-l-tyrosine as substrate. The predominant formation of E_met·I was confirmed from a long prolongation of lag time and a decrease of the static state activity of the enzyme. All tested compounds had a significant binding affinity to tyrosinase with K_SV values of 0.06–0.27 × 10⁴ L·mol⁻¹, which are well correlated with IC₅₀s. In kinetic study, all flavonolignan (1–7) were mixed type I (K_I < K_IS) inhibitors, whereas their mother skeletons (8–10) were competitive ones. The UPLC-ESI-TOF/MS analysis showed that the isolated inhibitors are the most abundant metabolites in the target plant.     

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.     

Synthesis of a ‘direct-linked’ C-disaccharide from a pyranulose glycoside

Syntheses of five ‘direct linked’ C-disaccharides 8a–e were reported. The (Et₃SiH/BF₃·Et₂O) reduction of pyranulose glycoside 1 yielded (6S)- and (6R)-6-(2,3,5-tri-O-benzoyl-β-d-ribofuranosyl)pyran-3(2H,6H)-one (2a and 2b) in a ratio of ca. 2:1 and in 88% combined yield. The absolute stereochemistry of each was determined from its CD spectrum. The reduction of 2a with NaBH₄ in methanol afforded two allylic alcohols 6a and 6b in 14 and 73% yield, respectively. The reduction of 2b with NaBH₄ afforded 6c and 6d in 30 and 56% yield, respectively. Cis hydroxylation of the double bond in compounds 6a–d with osmium tetroxide gave 7a–e. The stereoisomers 7a–e were separated and their configuration was established by ¹H NMR spectroscopy. Debenzoylation of compounds 7a–e with aqueous sodium carbonate produced deprotected C-disaccharides 8a–e.     

New C9-polyacetylenes from the essential oil of the highly endangered species Baccharis palustris Heering (Asteraceae)

The essential oil composition of the aerial parts from Baccharis palustris Heering (Asteraceae), a highly endangered species, was analyzed by GC/qMS, GC/HRMS-TOF, FT-IR, UV–vis and NMR spectroscopy using 1D and 2D techniques. To our knowledge, this is the first report on the essential oil composition of B. palustris, as well as the first phytochemical study on this plant species. The volatile extracts were obtained from different phenologicals stages of plant, at flowering stage (FS) and vegetative stage (VS), where 51 components were identified accounting for 96.3 % and 99.0 % of the oil, respectively. The oil was rich in polyacetylene compounds (> 75 %), being the main components identified the new natural C₉-polyacetylenes 1-nonene-3,5-diyne (1, here named as baccharisdiyne) (52.7–65.0 %), 1,7(Z)-nonadiene-3,5-diyne [2, 7(Z)-dehydro-baccharisdiyne] (14.4–17.8 %), and 1,7(E)-nonadiene-3,5-diyne [3, 7(E)-dehydro-baccharisdiyne] (1.5–2.4 %). In addition, the known polyacetylenic compounds (Z)-lachnophyllum acid methyl ester (4) (4.3–5.3 %) and (E)-lachnophyllum acid methyl ester (5) (0.2 %) were also identified. Moreover, GC/qMS analysis allowed the identification of other 46 components in the essential oil samples, mainly mono- and sesquiterpenoids. In B. palustris, C₉-polyacetylenes probably derive biogenetically from a C₁₀ precursor: baccharisdiyne (1) would be derived from either or both lachnophyllum methyl ester geometric isomers (4 or 5), by enzymatic hydrolysis followed by decarboxylation. Dehydro-baccharisdiynes (2 and 3) could be produced by a similar pathway starting from the corresponding matricaria acid methyl ester isomers, one of which was tentatively identified at trace-level in B. palustris essential oil.     

Rubiyunnanins C-H, cytotoxic cyclic hexapeptides from Rubia yunnanensis inhibiting nitric oxide production and NF-κB activation

Six new (rubiyunnanins C–H, 1–6) and five known (7–11) cyclic hexapeptides were isolated from the roots of Rubia yunnanensis (Franch.) Diels. The structures and stereochemistry of 1–6 were established by extensive spectroscopic analyses and chemical methods. All compounds (1–11) not only exhibited cytotoxic activities against a panel of eleven cancer cell lines with IC₅₀ values ranging from 0.001 to 56.24 μM, but also exerted inhibitory activities against nitric oxide (NO) production in LPS and IFN-γ-induced RAW 264.7 murine macrophages with IC₅₀ values ranging from 0.05 to 12.68 μM. Furthermore, this is the first time it is being reported that compounds 2 and 7–10 significantly inhibited TNF-α-induced NF-κB activation in HEK-293-NF-κB luciferase stable cells with IC₅₀ values of 35.07, 0.03, 1.69, 12.64 and 1.18 μM, respectively.     

Steroidal alkaloids from Solanum erianthum and their anti-breast cancer properties

Two new glycoalkaloids, erianosides A (1) and B (2) along with five known compounds (3–7) were isolated from the leaves of Solanum erianthum. Their structures were elucidated from analyses of spectroscopic data and all isolates were tested for in vitro cytotoxic activity against human breast cancer cell lines (BT-549, MDA-MB-231, T74D, and MCF-7). Solasonine (5) and solamargine (6) were active against the aforementioned four cancer cell lines with IC₅₀ values of 27.26–35.89 and 5.84–10.13 μM, respectively. Erianoside A (1) (T74D: IC₅₀, 56.39 µM) and solasodine (3) (BT-549 and MDA-MB-231: IC₅₀, 59.15 and 75.63 µM, respectively) had moderate cytotoxic effects towards some cell lines in the panel.     

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7–12 (series A), N,S-dimethyl-dihydropyrimidines 13–18 (series B), hydrazine derivatives of dihydropyrimidine 19–24 (series C), and tetrazolo dihydropyrimidine derivatives 25–30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B–D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC₅₀ values between 34.7–42.9 and 15.0–26.0 μM, respectively. The structure–activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7–12) and C (19–24) were carried out to determine their modes of inhibition and dissociation constants K_i. Compounds of series A (7–12) and series C (19–24) showed a mixed-type of inhibition with K_i values ranging between 15.76–25.66 and 14.63–29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A–D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.     

Neuroprotective effects of triterpenoid saponins from Medicago sativa L. against H2O2-induced oxidative stress in SH-SY5Y cells

Medicago sativa L. is a forage legume plant widely distributed in all continents. Six new triterpenoid saponins, Medicagosides A-F (1–6) and five known ones (7–11) were isolated from M. sativa. Their structures were determined via HRESIMS, 1D and 2D NMR analysis. Biologically, all the isolates displayed neuroprotective activities against H₂O₂-induced damage in SH-SY5Y cells. Among them, compounds 1, 3–5 and 10 exhibited striking neuroprotective activities at 100 μM, restoring cell viability range from 79.66% to 89.03%, relative to 79.46% (100 μM) of Trolox used as the positive control.     

Cytotoxic withanolides from the aerial parts of Tubocapsicum anomalum

Ten new withanolides (1–10) and three artificial withanolides (11–13) were isolated from the aerial parts of Tubocapsicum anomalum, together with five known analogues (14–18). Their structures were determined on the basis of extensive spectroscopic and chemical methods. They include seven acnistin–type (1–4, 11, 14 and 15), three withajardin–type (5–7), and eight normal–type (8–10, 12, 13 and 16–18) withanolides. Of normal–type withanolides, a chemical conversion from the 16α,17α–epoxywithanolide (16) to Δ^13,14–16α–hydroxywithanolide (18) was achieved by Wagner–Meerwein rearrangement. All isolates were evaluated for their cytotoxicity against four human tumor cell lines (HCT–116, HepG2, MCF–7 and A375). Among them, compounds 1–3, 6–8, 14, 16–18 showed cytotoxic activity with IC₅₀ values of 0.24–8.71 μM.     

Synthesis and properties of some O-[2,2-bis(alkylthio)ethyl]-glycolaldehydes

O-[2,2-Bis(alkylthio)ethyl]glycoaldehydes (1a–e; alkyl = Et, Pr, Prⁱ, Bu^t, and -CH₂-, respectively) have been prepared from the corresponding O-[2,2-bis(alkylthio)ethyl]glycolaldehyde dimethyl acetals (2a–e) by acid hydrolysis. In anhydrous 1,4-dioxane in the presence of BF₃ · (Et₂O)₂,1a–c were partially transformed into glycolaldehyde bis(dialkyl dithioacetals),1d afforded trans-2,6-bis(tert-butylthio)-1,4-dioxane and 3,5-bis(tert-butylthio)-1,4-oxathiane, and1e did not react. The acetals2a–e) were prepared from the appropriate glycolaldehyde dialkyl dithioacetal by O-alkylation with bromoacetaldehyde dimethyl acetal.     

Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors

Four bis-N-n-propyl analogues (3–6) in the uracil ring of two hybrid molecules (1 and 2) of caffeine and eudistomin D, a β-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A₁, A_2A, and A₃ were examined. All the compounds (3–6) showed better potency as adenosine receptor ligands than caffeine. Bis-N-n-propylation (3 and 4, respectively) of the uracil ring in 1 and 2 resulted in higher affinity for A₁ and A_2A adenosine receptors. Furthermore, it was found that a compound (5) possessing a n-propyloxy group at C-7 in compound 3 with a nitrogen at the β-position of the pyridine ring (β-N type) enhanced remarkably affinity for adenosine receptor A₃ subtype, while n-propyloxy substitution (compound 6) at C-5 in compound 4 with a nitrogen at the δ-position of the pyridine ring (δ-N type) reduced affinity for all the adenosine receptor, A₁, A_2A, and A₃. Among all the compounds (1–6) examined, compound 5 showed the most potent affinity for adenosine receptor A₃ subtype (K_i value, 0.00382 μM).     

Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s bases incorporating benzenesulfonamide,methanesulfonamide, and methylsulfonylbenzene scaffolds

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (K_I) in the range 93.5–428.1 nM (AAZ and SLC-0111: K_I, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with K_I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K_I, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with K_I in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K_I, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with K_I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K_I, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.     

Competitive neutrophil elastase inhibitory isoflavones from the roots of Flemingia philippinensis

Flemingia philippinensis has been used throughout history to cure rheumatism associated with neutrophil elastase (NE). In this study, we isolated sixteen NE inhibitory flavonoids (1–16), including the most potent and abundant prenyl isoflavones (1–9), from the F. philippinensis plant. These prenyl isoflavones (2, 3, 5, 7, and 9) competitively inhibited NE, with IC₅₀ values of 1.3–12.0 μM. In addition, they were reversible, simple, slow-binding inhibitors according to their respective parameters. Representative compound 3 had an IC₅₀ = 1.3 μM, k₃ = 0.04172 μM⁻¹ min⁻¹, k₄ = 0.0064 min⁻¹, and K_i^app = 0.1534 μM. The K_ik/K_iv ratios (18.5 ∼ 24.6) for compound 3 were consistent with typical competitive inhibitors. The prenyl functionality of isoflavones significantly affected inhibitory potencies and mechanistic behavior by shifting the competitive mode to a noncompetitive one. The remaining flavonoids (10–16) were confirmed as mixed type I inhibitors that preferred to bind free enzyme rather than the enzyme-substrate complex. Fluorescence quenching analyses indicated that the inhibitory potency (IC₅₀) closely followed the binding affinity (K_SV).     

Compounds from the fruits of Nicandra physaloides and their potential anti-inflammatory activities

Twenty-one compounds were isolated and identified from the ethanol extract of the fruits of Nicandra physaloides, including four new (1–4) and 17 known compounds (5–21). All the compounds were isolated from the genus Physalis for the first time. In this study, NMR spectroscopy was used to study the compound structures by comparing their data with those reported in the literature. Moreover, the potential anti-inflammatory activity of RAW264.7 cells induced by lipopolysaccharide (LPS) was evaluated. Among the monoterpenoids, compounds (5–7, 9) exhibited weak anti-inflammatory activities, with IC₅₀ values ranging from 29.10 to 68.30 μM.     

A new cerebroside and bioactive compounds from Celtis adolphi-friderici Engl. (Cannabaceae)

A phytochemical investigation of the roots of Celtis adolphi-friderici Engl. led to the isolation of a previously undescribed cerebroside named, eloundemnoside (1), alongside with seventeen known compounds (2–18). Their chemical structures were elucidated based on the analysis of their NMR and MS data. All the compounds were isolated from this specie for the first time, while eight known compounds (4–5, 12–13, 15–18) are obtained from the genus Celtis for the first time. The isolates were screened for their antioxidant, lipoxygenase, urease, and butyrylcholinesterase enzyme inhibitory activities. Compounds 4, 7 and 12 showed good antioxidant activities with IC₅₀ values of 22.2, 29.3, and 13.2 μM, respectively. In addition, azelaic acid (12) showed the best lipoxygenase inhibition (IC₅₀ value of 16.3 μM), while friedelin (2) exhibited the highest inhibition of urease with an IC₅₀ value of 15.3 μM. However, all the compounds tested had moderate butyrylcholinesterase inhibitory properties. The chemophenetic relationship of the isolates and their significance were discussed.     

Xanthones from the stem bark of Garcinia bracteata with growth inhibitory effects against HL-60 cells

Five xanthones, 1,4,5,6-tetrahydroxyxanthone (1) and bracteaxanthones III–VI (2–5) together with twenty-six known compounds (6–31), were isolated from the ethanol extract of the stem bark of Garcinia bracteata. Their structures were elucidated via spectroscopic analyses. Growth inhibitory activities of these compounds against the human leukaemic HL-60 cell line were measured in vitro. Compounds 7, 11, and 29 exhibited moderate activities with GI₅₀ values of 2.8, 3.4, and 3.1 μM, respectively, and a preliminary structure–activity relationship is discussed.     

Novel 8-(furan-2-yl)-3-substituted thiazolo [5,4-e][1,2,4] triazolo[1,5-c] pyrimidine-2(3H)-thione derivatives as potential adenosine A2A receptor antagonists

Novel thiazolotriazolopyrimidine derivatives (23–33) designed as potential adenosine A_2A receptor (A_2AR) antagonists were synthesized. Molecular docking studies revealed that all compounds (23–33) exhibited strong interaction with A_2AR. The strong interaction of the compounds (23–33) with A_2AR in silico was confirmed by their high binding affinity with human A_2AR stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24–26 demonstrated substantial binding affinity and selectivity for A_2AR as compared to SCH58261, a standard A_2AR antagonist. Decrease in A_2AR-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A_2AR antagonist potential of the compounds 24–26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24–26 further supports their role in the alleviation of PD symptoms.     

Nitric oxide inhibitory constituents from Siegesbeckia pubescens

Two new sesquiterpenoids (1 and 2) and a new ent-pimarane type diterpenoid (3), together with eighteen known compounds (4–21), were isolated from the whole plants of Siegesbeckia pubescens. The structures of the new compounds were determined on the basis of 1D-, 2D NMR and HRESIMS data. All compounds were evaluated for their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages. Of these, highly oxygenated germacrane type sesquiterpenoids (1–2 and 13–14) showed significant inhibitory effects with IC₅₀ values ranging from 3.9 to 16.8 μM.