Nitric oxide inhibitory principles from Derris trifoliata stems

Nine rotenoids were isolated from the hexane and dichloromethane extracts of Derris trifoliata stems and were tested for nitric oxide (NO) inhibitory activity using RAW264.7 cells. The result indicated that 12a-hydroxyrotenone (7) possessed very potent NO inhibitory activity with an IC₅₀ value of 0.002 μM, followed by 1 (deguelin, IC₅₀=0.008 μM), 9 (12a-hydroxyelliptone, IC₅₀=0.010 μM) and 2 (α-toxicarol, IC₅₀=0.013 μM), respectively. In addition, the DPPH scavenging activity of rotenoids was also investigated. It was found that 6a,12a-dehydrodeguelin (5) possessed the highest activity against DPPH with an IC₅₀ value of 7.4 μM, followed by deguelin (1, IC₅₀=27.4 μM). All compounds did not show any cytotoxicity at their IC₅₀ values for NO inhibitory activity.Structure–activity relationships (SARs) of these rotenoids against NO release are as follows: (1) hydroxylation at C12a dramatically increased activity, (2) prenylation at furan ring increased activity markedly and (3) hydrogenation of a double bond at C6a–C12a conferred higher activity. For the DPPH radical scavenging effect, it was found that (1) introduction of a double bond at C6a–C12a increased activity and (2) hydroxylation of C11 at the D-ring decreased activity. As regards active compounds of Derris trifoliata stems, the isolated compounds are responsible for the NO inhibitory effect, especially 7, 1, 9 and 2, whereas 5 and 1 are those for the DPPH scavenging activity.     

Anti-inflammatory components of Euphorbia humifusa Willd.

Two new compounds, euphorbinoside (1) and dehydropicrorhiza acid methyl diester (2), along with 24 known compounds (3–26) were isolated from Euphorbia humifusa Willd. The effects of these compounds on soluble epoxide hydrolase (sEH) inhibitory activity were evaluated. Flavonoid compounds (10–21) exhibited high sEH inhibitory activity. Among them, compounds 12, 13, and 19 greatly inhibited sEH enzymatic activity, with IC₅₀ values as low as 18.05 ± 1.17, 18.64 ± 1.83, and 17.23 ± 0.84 μM, respectively. In addition, the effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) production by RAW 264.7 cells were investigated. Compounds 3–6, 8, 18, 20–23, and 25–26 inhibited the production of both NO and TNF-α, with IC₅₀ values ranging from 11.1 ± 0.9 to 45.3 ± 1.6 μM and 14.4 ± 0.5 to 44.5 ± 1.2 μM, respectively.     

Synthesis and cytotoxic activity of nitric oxide-releasing isosteviol derivatives

Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC₅₀ = 4.24 μM) and 18d (IC₅₀ = 2.75 μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC₅₀ = 4.99 μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC₅₀ = 2.78 μM) and CDDO-Me (IC₅₀ = 5.85 μM), particularly, 10b (IC₅₀ = 0.02 μM) presented the strongest effect, which was selected as a candidate for further study.     

Daphnane-type diterpenes with inhibitory activities against human cancer cell lines from Daphne genkwa

Four new daphnane-type diterpenes, genkwadanes A–D (1–4), together with 19 known ones, were isolated from ethanol extract of the flower buds of Daphne genkwa. Their structures were determined on the basis of extensive spectroscopic data. Among them, daphnane-type diterpene with a 1,10-double bond (1) was isolated from this plant for the first time. The cytotoxicity of all compounds 1–23 against the 10 selected human cancer cell lines was assayed. A number of compounds exhibited significant activities against the 10 cancer cell lines (IC₅₀ < 9.56 μM). and most interestingly, all the compounds revealed preferred cytotoxicities on the HT-1080 cell line and displayed much stronger inhibitory activities (IC₅₀ < 29.94 μM) compared with positive control 5-fluorouracil (IC₅₀ = 35.62 μM), particularly, compounds 9–11, 13, 16 and 19 exhibited the strongest cytotoxicity activities against the HT-1080 cell line (IC₅₀ < 0.1 μM).     

Three new geranyl aurones from the leaves of Artocarpus altilis

From the MeOH extract of the leaves of Artocarpus altilis (Moraceae), three new aurones, altilisin H (1), I (2), and J (3), have been isolated together with two known flavonoids. Their structures were elucidated on the basis of spectroscopic data. All compounds possessed tyrosinase inhibitory activity with IC₅₀ values less than 100 μM, while compounds 1–3 displayed potent α-glucosidase inhibitory activity with IC₅₀ values ranging from 4.9 to 5.4 μM.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Synthesis and biological activity of 4-substituted benzoxazolone derivatives as a new class of sEH inhibitors with high anti-inflammatory activity in vivo

A series of novel 4-substituted benzoxazolone derivatives was synthesized, characterized and evaluated as human soluble epoxide hydrolase (sEH) inhibitors and anti-inflammatory agents. Some compounds showed moderate sEH inhibitory activities in vitro, and two novel compounds, 3g and 4j, exhibited the highest activities with IC₅₀ values of 1.72 and 1.07 μM, respectively. Structure–activity relationships (SARs) revealed that introduction of a lipophilic amino acid resulted in an obvious increase in the sEH inhibitory activity, especially for derivatives containing a phenyl (3d, IC₅₀ = 2.67 μM), pyrrolidine (3g, IC₅₀ = 1.72 μM), or sulfhydryl group (3e, IC₅₀ = 3.02 μM). Several compounds (3a–3g) were tested in vivo using a xylene-induced ear edema mouse model. Three compounds (3d, 3f, and 3g) showed strong anti-inflammatory activities in vivo which were higher than that of Chlorzoxazone, a reference drug widely used in the clinic. Our investigation provided a novel type of sEH inhibitor and anti-inflammatory agent that may lead to the discovery of a potential candidate for clinical use.     

Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis

We isolated 18 polyphenols with neuraminidase inhibitory activity from methanol extracts of the roots of Glycyrrhiza uralensis. These polyphenols consisted of four chalcones (1–4), nine flavonoids (5–13), four coumarins (14–17), and one phenylbenzofuran (18). When we tested the effects of these individual compounds and analogs thereof on neuraminidase activation, we found that isoliquiritigenin (1, IC₅₀ = 9.0 μM) and glycyrol (14, IC₅₀ = 3.1 μM) had strong inhibitory activity. Structure–activity analysis showed that the furan rings of the polyphenols were essential for neuraminidase inhibitory activity, and that this activity was enhanced by the apioside group on the chalcone and flavanone backbone. In addition, the presence of a five-membered ring between C-4 and C-2′ in coumestan was critical for neuraminidase inhibition. All neuraminidase inhibitors screened were found to be reversible noncompetitive inhibitors.     

Ellagitannin and flavonoid constituents from Agrimonia pilosa Ledeb. with their protein tyrosine phosphatase and acetylcholinesterase inhibitory activities

A new ellagitannin, agritannin (1), a new flavone glycoside, agriflavone (2), and another flavone glycoside with spectroscopic data reported for the first time, kaempferol-3-O-[(S)-3-hydroxy-3-methylglutaryl (1→6)]-β-d-glucoside (3), along with 16 known compounds were isolated from the aerial parts of Agrimonia pilosa Ledeb. These compounds were evaluated for PTP1B inhibitory activity. Among them, compounds 9 and 18 displayed potential inhibitory activity against PTP1B with IC₅₀ values of 7.14 ± 1.75 and 7.73 ± 0.24 μM, respectively. In addition, compound 1 showed significant inhibitory effect with an IC₅₀ value of 17.03 ± 0.09 μM. Furthermore, these compounds were tested in AChE inhibitory assays. Most of them were found to have moderate inhibitory effects, with IC₅₀ values ranging from 60.20 ± 1.09 to 92.85 ± 1.12 μM. Except compounds 3, 8, and 18 were inactive.     

Cytotoxic triterpene saponins from the stem bark of Kalopanax pictus

Three new compounds, 3β,6β,23-trihydroxyolean-12-en-28-oic acid 3-O-α-l-arabinopyranoside (1), kalopanaxsaponin L (2), and kalopanaxsaponin M (13), as well as eleven known compounds (3–12 and 14), were isolated from the stem bark of Kalopanax pictus. Their structures were determined on the basis of extentive spectroscopic analyses and acid hydrolysis. The cytotoxicity of the compounds was evaluated in three human carcinoma cell lines, including HL-60, HCT-116, and MCF-7. Compounds 1, 5–8, 10, and 11 exhibited significantly cytotoxic activity toward HL-60 cells, with IC₅₀ values ranging from 0.1 to 6.9 μM. Compounds 4–7 and 14 showed significant cytotoxicity against HCT-116 cells, with IC₅₀ values ranging from 0.4 to 9.2 μM. Remarkably, the cytotoxic activities of compounds 5–7 against HCT-116 cells were greater than that of the anticancer chemotherapy drug, mitoxantrone (IC₅₀ = 3.7 μM). Compounds 1, 3, 5, and 14 were cytotoxic toward MCF-7 cells with IC₅₀ values in a range of 7.4–14.5 μM.     

Triterpenoid saponins from Clematis chinensis and their inhibitory activities on NO production

Four new triterpenoid saponins, clematochinenoside H–K (1–4), and five known structures (5–9), were isolated from the roots and rhizomes of Clematis chinensis. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis products. All isolates were evaluated for inhibitory effects against nitric oxide (NO) production in LPS-induced RAW 246.7 macrophages. Monodesmosidic saponins (1–3, 5, and 6) with a free carboxylic acid function at C-28 exhibited potent inhibitory activities with IC₅₀ values in the range of 12.9–32.3 μM, where as bisdesmosidic saponin (4, and 7–9) showed modest inhibitory effects with the inhibition ratios (%) from 39.9 to 59.0 at 50 μM. In addition, the hydroxyl group at C-21 showed negative effect on the NO production inhibitory activity.     

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).     

Synthesis and biological evaluation of 3′,4′,5′-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation

A series of 23 3′,4′,5′-trimethoxychalcone analogues was synthesized and their inhibitory effects on nitric oxide (NO) production in LPS/IFN-γ-treated macrophages, and tumor cell proliferation has been investigated. 4-Hydroxy-3,3′,4′,5′-tetramethoxychalcone (7), 3,4-dihydroxy-3′,4′,5′-trimethoxychalcone (11), 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (14), and 3,3′,4′,5′-tetramethoxychalcone (15) were the most potent growth inhibitory agents on NO production, with an IC₅₀ value of 0.3, 1.5, 1.3 and 0.3 μM, respectively. The tumor cells proliferation assay results revealed that several compounds exhibited potent inhibition activity against different cancer cell lines. The chalcone 15 was the most potent anti-proliferative compound in the series with IC₅₀ values of 1.8 and 2.2 μM toward liver cancer Hep G2 and colon cancer Colon 205 cell lines, respectively. 2,3,3′,4′,5′-Pentamethoxychalcone (1), 3,3′,4,4′,5,5′-hexamethoxychalcone (3), 2,3′,4,4′,5,5′-hexamethoxychalcone (5), 2-hydroxy-3,3′,4′,5′-tetramethoxychalcone (10), 11 and 14 showed significant anti-proliferation actions in Hep G2 and Colon 205 cells with an IC₅₀ values ranging between 10 and 20 μM. Among the tested agents, compound 7 showed selective NO production inhibition (IC₅₀ = 0.3 μM), while has no effect on tumor cell proliferation (IC₅₀ >100 μM). 3,3′,4,4′,5′-Pentamethoxychalcone (2) showed selective anti-proliferation effect in Hep G2 cells, in addition to its potent NO inhibition, however has no such response in Colon 205 cells. In contrast, 3-formyl-3′,4′,5′-trimethoxychalcone (22) showed moderate growth inhibition in Colon 205 cells, while has no such effect on NO production and Hep G2 cells proliferation. These results provide insight into the correlation between some structural properties of 3′,4′,5′-trimethoxychalcones and their in vitro anti-inflammatory and anti-cancer differentiation activity.     

Potential anti-inflammatory phenolic glycosides from the medicinal plant Moringa oleifera fruits

Bioassay-guided isolation and purification of the ethyl acetate extract of Moringa oleifera fruits yielded three new phenolic glycosides; 4-[(2′-O-acetyl-α-l-rhamnosyloxy) benzyl]isothiocyanate (1), 4-[(3′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (2), and S-methyl-N-{4-[(α-l-rhamnosyloxy)benzyl]}thiocarbamate (3), together with five known phenolic glycosides (4–8). The structures of the new metabolites were determined on the basis of spectroscopic analyses including 1D- and 2D-NMR and mass spectrometry. The anti-inflammatory activity of isolated compounds was investigated with the lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cell line. It was found that 4-[(2′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (1) possessed potent NO–inhibitory activity with an IC₅₀ value of 1.67 μM, followed by 2 (IC₅₀ = 2.66 μM), 4 (IC₅₀ = 2.71 μM), and 5 (IC₅₀ = 14.4 μM), respectively. Western blots demonstrated these compounds reduced LPS-mediated iNOS expression. In the concentration range of the IC₅₀ values, no significant cytotoxicity was noted. Structure–activity relationships following NO-release indicated: (1) the isothiocyanate group was essential for activity, (2) acetylation of the isothiocyanate derivatives at C-2′ or at C-3′ of rhamnose led to higher activity, (3) un-acetylated isothiocyanate derivatives displayed eight times less activity than the acetylated derivatives, and (4) acetylation of the thiocarbamate derivatives enhanced activity. These data indicate compounds 1, 2, 4 and 5 are responsible for the reported NO-inhibitory effect of Moringa oleifera fruits, and further studies are warranted.     

Synthesis of novel pyrazole–thiadiazole hybrid as potential potent and selective cyclooxygenase-2 (COX-2) inhibitors

A series of 1,3,4-trisubstituted pyrazole derivatives (3a–f), (4a–f), and (5a–f) have been synthesized and evaluated for their cyclooxygenase (COX-1 and COX-2) inhibitory activity. The structures of newly synthesized compounds were characterized by IR, ¹H NMR, and mass spectral analysis. All of the compounds showed good inhibition of COX-2 with IC₅₀ of 1.33–17.5 μM. Among these derivatives, compound (5c) was the most potent and selective COX-2 inhibitor (IC₅₀ = 1.33 μM), with a significant selectivity index (SI >60). Molecular docking studies were carried out in order to predict the hypothetical binding mode of these compounds to the COX-2 isoenzyme. The result of present study suggests that pyrazole–thiadiazole hybrid could be an interesting approach for the design of new selective COX-2 inhibitory agents.     

New phenolic glycosides with cyclooxygenase inhibition from the roots of Tecoma mollis

Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC₅₀ 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC₅₀ values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines.     

Identification and evaluation of apoptotic compounds from Garcinia paucinervis

Four new compounds, paucinervins A–D (1–4), and 15 known ones were isolated from the leaves of Garcinia paucinervis. The structures of the new compounds were elucidated by spectroscopic evidences. All of the 19 compounds were evaluated for their apoptosis-inducing effects using HeLa-C3 cells which have been genetically engineered to possess a fluorescent biosensor capable of detecting caspase-3 activation. Eight of them were found to activate caspase-3 in HeLa-C3 cells within 72 h at the concentration of 25 μM. Moreover, the values of IC₅₀ were measured for all four new compounds on HeLa cells using the MTT assay. Among them, compound 2 (paucinervin B) had the lowest IC₅₀ value of 9.5 μM, while the other three new compounds had much higher IC₅₀ values of 29.5, 52.5, and 95.6 μM, respectively. This result shows that paucinervin B has the strongest inhibitory effect against HeLa cell growth among these four newly identified paucinervins and it may have the potential to be developed into a new anticancer candidate.     

Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs

Hybrid bisindole-thiosemicarbazides analogs (1–18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC₅₀ values ranging from 0.1 to 5.7 μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC₅₀ values ranging from 7.12 to 15.0 μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC₅₀ values 33.2 ± 0.75, 21.4 ± 0.30 and 28.12 ± 0.25 μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds.     

A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids and evaluation of their antimycobacterial,anticancer and AchE inhibitory activities

A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC₅₀ 1.07 μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC₅₀ <1.56 μM) and 6l (IC₅₀ = 2.87 μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC₅₀ values of 1.10 and 1.16 μmol/L respectively.     

A novel sesquiterpene quinone from Hainan sponge Dysidea villosa

A new sesquiterpene quinone, 21-dehydroxybolinaquinone (5), together with two known related analogues, bolinaquinone (6) and dysidine (7), had been isolated from the Hainan sponge Dysidea villosa. The structure of the new compound 5 was elucidated on the basis of detailed analysis of spectroscopic data and by comparison with related model compounds. Compounds 5–7 were evaluated for the inhibitory activity against hPTP1B, a potential drug target for treatment of type-II diabetes and obesity, and cytotoxic activity against Hela cell line. The results showed that dysidine (7) had the strongest hPTP1B inhibitory activity with an IC₅₀ value of 6.70 μM and 6 had significant cytotoxic activity against Hela cell line with an IC₅₀ value of 5.45 μM. New compound 5 showed moderate PTP1B inhibitory activity and cytotoxicity with IC₅₀ values of 39.50 and 19.45 μM, respectively.