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.     

Aethusifolins A–D: Four new components from a traditional Mongolian medicinal herb Clematis aethusifolia Turcz

Four new components named aethusifolins A–D (1–4), together with ten known (5–14) were isolated from the dried aerial parts of a traditional Mongolian medicinal herb Clematis aethusifolia Turcz. The planar structures were established based on extensive spectroscopic analysis (HRMS, 1D and 2D NMR), and the absolute configurations were determined by modified Mosher’s method, hydrolysis method. The cytotoxicities of isolated compounds against a panel of five human solid tumor cell lines were assayed. Compounds 5, 8, and 13 showed moderate cytotoxicity against A-375 with IC₅₀ values of 15–18 μM, while compound 8 also showed cytotoxicity against SH-SY5Y with IC₅₀ values of 20 μM.     

Artostyracins A–C,three new isoprenylated 2-arylbenzofurans from Artocarpus styracifolius

Three new isoprenylated 2-arylbenzofurans, namely artostyracins A–C (1–3, resp.), together with a known one (4), were isolated from the root of Artocarpus styracifolius Pierre. Their structures were determined by spectroscopic methods (1D and 2D NMR, UV, IR, and HR-ESI-MS). All of the compounds were evaluated for the anti-respiratory burst properties using a cellular model reproduced by chemical stimulation of rat neutrophils. Compounds 1 and 3 offered the potently inhibitory effects on respiratory burst of rat neutrophils with IC₅₀ values of 1.42 and 1.91 μM, while compounds 2 and 4 revealed moderate suppression activity with IC₅₀ values of 11.56 and 46.91 μM.     

Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities

Seven eremophilane-type sesquiterpenes (1–7), six cycloartane derivatives (8–13) and α-amyrin acetate (14) were isolated from the leaves of the far-eastern plant Ligularia alticola Worosch. (Family Asteraceae). (4S,5R,8S,10R)-8-Ethoxyeremophil-7(11)-en-12(8)-olide (1), 8α,11-epidioxy-8β-methoxyeremophil-6-ene (2) and 29-norcycloartan-3α-ol (8) have not been previously reported. Fukinone α-epoxide (3) was isolated for the first time from a natural source. The structures of all the compounds were established by the extensive analysis of their 1D and 2D NMR spectra and HR ESI mass spectrometry. The absolute stereochemistry of 1 was determined by comparison of theoretical and experimental ECD spectra with the application of B3LYP-TDDFT and B3LYP-GIAO calculations as well as by NMR spectroscopy. Compound 1 showed cytotoxic action against human cancer HL-60, Raji, and THP-1 cell lines (IC₅₀ 12.6, 6.0 and 6.9 μM, respectively). Compounds 2 and 4 demonstrated significant cytotoxic activities against HL-60 (IC₅₀ 2.8 and 5.8 μM, respectively) and Raji cells (IC₅₀ 2.9 and 4.2 μM, respectively). Compound 6 was cytotoxic against Raji cells (IC₅₀ 4.6 μM). None of tested compounds were cytotoxic against RAW 264.7 cells. Compounds 1 and 4–7 significantly decreased intracellular ROS levels, induced by endotoxic LPS from Escherichia coli in RAW 264.7 murine macrophages.     

β-Secretase (BACE1)-inhibiting C-methylrotenoids from Abronia nana suspension cultures

Suspension cultures of Abronia nana were established to produce C-methylisoflavones. A new C-methylrotenoid, named abronione A (2), was isolated along with three known rotenoids, boeravinone D (1), boeravinone A methyl ether (3), and mirabijalone D (4). The IC₅₀ values of compounds 1, 2, and 4 on β-secretase (BACE1) were 4.77, 62.21, and 4.24 μM, respectively, whereas 3 was inactive. At concentrations up to 1.0 mM, the compounds did not inhibit other proteases such as trypsin, chymotrypsin, and elastase, indicating that they were specific inhibitors of β-secretase. Compounds 1 and 4 were non-competitive inhibitors based on the Dixon plot and with K_i values of 5.01 and 4.28 μM, respectively. At 50 μM, compound 4 inhibited Aβ_1–42 production by 43.7% in APP_SW-N2a cells.     

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.     

Design,synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors

A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC₅₀ values of 0.14?μM and 0.86?μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25?μM and HBV cccDNA (covalently closed circularDNA) replication with IC₅₀ values of 33.5?μM, 32.7?μM and 12.3?μM respectively.     

Antidiabetic triterpenoids from the leaves of Paeonia suffruticosa and Paeonia delavayi

Three new nor-oleanane triterpenoids, paeonenoides I-K (1-3), together with 13 known triterpenoids including nor-oleanane, oleanane, ursane, and cycloartane types, were isolated from the leaves of Paeonia suffruticosa and P. delavayi. The structures of the new compounds were elucidated with the aid of HRESIMS, 1D and 2D NMR, IR, and [α]_D spectroscopic methods. Nine compounds (5-6, 8-11, 13-14 and 16) showed inhibition against PTP1B with IC₅₀ values ranging from 36.5 to 192.6 μM, six compounds (5-6, 8-10 and 14) exhibited inhibitory activity against GPa with IC₅₀ values ranging from 39.8 to 108.0 μM, and five compounds (1, 6, 10, 15 and 16) could significantly stimulate GLP-1 secretion by 100.2–313.4% (20 μM). Docking study demonstrated that compounds 5 and 6 strongly bonded with Gpa and PTP1B by salt bridges, hydrogen bonds and hydrophobic interactions, verifying the importance of carboxyl and hydroxyl groups. Especially, compounds 5 and 14 could simultaneously inhibit PTP1B and GPa with IC₅₀ values of 57.8, 47.9 μM and 39.8, 45.2 μM, and compounds 6 and 10 could stimulate GLP-1 secretion by 293.6% and 313.4% at 20 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.     

Tirucallane triterpenoids from the stem bark of Araliopsis synopsis

Two new tirucallane triterpenoids, 21-methoxy-21,23-epoxy-tirucalla-7,24-dien-3α-ol (1) and 21-methoxy-21,23-epoxy-tirucalla-7,24-diene-1α,3α-diol (2), together with thirteen known compounds were isolated from the CH₂Cl₂ extract of the stem bark of Araliopsis synopsis. The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data and comparison with previously known analogs. Compounds 1–10 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with MICs > 1 mg/mL. However, compounds 5–10 exhibited high cytotoxic activity against the human Caucasian prostate adenocarcinoma cell PC-3 line, with IC₅₀ 8.5–12.5 μM compared to the standard Doxorubicin with IC₅₀ = 0.9 μM, while compounds 1, 3 and 4 showed low activity.     

Design,synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors

A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC₅₀) values of 17 compounds against EGFR wt were less than 0.020 μM, and those of 12 compounds were less than 0.010 μM. The IC₅₀ values of 10 compounds against EGFR T790M/L858R were less than 0.005 μM. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1 μM. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1 μM), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method.     

Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor,DMAPT (LC-1)

A series of aminoparthenolide analogs (6–37) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD₅₀’s in the low μM range (1.5–3.0 μM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than 90% cell death at 10 μM concentration against primary AML cells in culture, with LD₅₀ values of 1.7, 1.8 and 1.6 μM.     

α-Glucosidase inhibitory and nitric oxide production inhibitory activities of alkaloids isolated from a twig extract of Polyalthia cinnamomea

The first phytochemical investigation of Polyalthia cinnamomea led to the isolation and identification of two new oxoprotoberberine alkaloids, (−)-(13aS)-polyalthiacinnamines A and B, together with eleven known compounds. The structures of the new compounds were elucidated by extensive spectroscopic methods. The absolute configuration of miliusacunine E and consanguine B was established by X-ray diffraction analysis using Cu Kα radiation and ECD spectra, whereas the absolute configurations of polyalthiacinnamines A and B were established by comparison of their ECD spectra and specific rotations with those of miliusacunine E and consanguine B. Compounds 1–4, 6, and 8 exhibited α-glucosidase inhibitory activities (IC₅₀ values ranging from 11.3 to 57.9 µM) better than a positive control (acarbose, IC₅₀ 83.5 μM). Compound 2 also exhibited NO production inhibitory activity with an IC₅₀ value of 24.4 μM (indomethacin, a positive control, IC₅₀ = 32.2 μM).     

New antimalarials with a triterpenic scaffold from Momordica balsamina

Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of three new cucurbitane-type triterpenoids, balsaminols C–E (1–3). Their structures were elucidated on the basis of spectroscopic methods including 2D NMR experiments (COSY, HMQC, HMBC and NOESY). Balsaminols C–E, together with ten cucurbitacins isolated from the same plant (4–13), were evaluated for their antimalarial activity against the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Most of the compounds displayed antimalarial activity. Compounds 9 and 12 revealed the highest antiplasmodial effects against both strains (IC₅₀ values: 4.6, and 7.4 μM, 3D7, respectively; 4.0, and 8.2 μM, Dd2, respectively). Structure–activity relationships are discussed. Furthermore, the preliminary toxicity toward human cells of compounds 1–5 and 9 was investigated in breast cancer cell line (MCF-7). Compounds were inactive or showed weak toxicity (IC₅₀ values >19.0).     

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.     

Two new ent-kaurane diterpenoids from the leaves of Sphagneticola trilobata

Two new ent-kaurane diterpenoids, namely 3α,16α-dihydroxy-ent-kauran-19-oic acid (1) and 3α,9β-dihydroxy-ent-kauran-19-oic acid (2), together with eight known compounds were isolated and identified from the leaves of Sphagneticola trilobata. Their structures were elucidated on the basis of extensive spectroscopic analysis including 1D, 2D NMR and MS techniques. Known compounds 4, 5 and 8−10 were obtained from S. trilobata for the first time. These compounds were tested for their in vitro α-glucosidase inhibitory activity and their tyrosinase inhibitory potential. Compounds 2, 3 and 6 were found to show in vitro α-glucosidase inhibitory activity with IC₅₀ values ranging from 0.398 to 0.476 mM, which were close or more potent than reference compound acarbose (IC₅₀ 0.410 mM). Compounds 2 and 6 were further revealed to show in vitro tyrosinase inhibitory activity (IC₅₀ 29.25 and 40.74 μM) but inferior to that of the positive control kojic acid (IC₅₀ 12.55 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).     

Acylated iridoid glycosides and acylated rhamnopyranoses from Gmelina arborea flowers

Nine acylated iridoid glycosides (1–9), five acylated rhamnopyranoses (10–14) and verbascoside (15) were isolated from Gmelina arborea flowers, including 5 new compounds (1, 2, and 10–12). The cytoprotective activity of 11 selected compounds (1–8, 10, 11, and 15) against CCl₄-induced cytotoxicity on liver was determined. Compounds 1, 2, 4, 7, 8 and 15 displayed hepatoprotective activity. 6-O-α-l-(2″, 3″-di-O-trans-p-hydroxycinnamoyl)rhamnopyranosylcatalpol (2) exhibited the most potent cytoprotective effect with an EC₅₀ value of 42.5 μM (SI = 19.3) compared with biphenyldimethylesterate (DDB, EC₅₀ = 277.3 μM, SI = 9.8) and bicylo-ethanol (EC₅₀ = 279.2 μM, SI = 12.2). Among the acylated iridoid glycosides, the compounds (2 and 8) containing phenolic hydroxy groups were more active than were those lacking them.     

The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies

Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objecctive of the present study was to evaluate effects of benzothiazole analogs (compounds 1–26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8–10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC₅₀ ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC₅₀ values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC₅₀ values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P < 0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC₅₀ range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases.