Chemical constituents from Taraxacum officinale and their α-glucosidase inhibitory activities

Three novel butyrolactones (1–3) and butanoates (4–6), namely taraxiroside A–F, were isolated from Taraxacum officinale along with twenty-two known compounds (7–28). Their chemical structures were elucidated by interpretation of spectroscopic data and comparison with those of literatures. All isolates were evaluated for their α-glucosidase inhibitory activities. Novel compounds 1–6 (IC₅₀ 145.3–181.3?μM) showed inhibitory activities similar to that of acarbose (IC₅₀ 179.9?μM). Compound 7 and 12 were the most potent inhibitor with IC₅₀ values of 61.2 and 39.8?μM respectively. Compounds 2 and 12 showed as mixed-type inhibition, whereas compound 7 and acarbose showed competitive inhibition.     

Design,synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC₅₀ values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC₅₀?=?<0.00050?μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC₅₀?=?<0.00050, 0.025, and 0.050?μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI₅₀?=?0.10?μM) related to acute myeloid leukemia (AML).     

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC₅₀ values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC₅₀ values of 1.1 μM, 0.92 μM and 8.77–14.3 μM. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.     

Anti-liver cancer constituents from the thorns of Gleditsia sinensis

Four new long-chain esters of trans-ferulic acid (1–4) were isolated from the thorns of Gleditsia sinensis, together with eight known compounds (5–13). The structure elucidations were achieved by in-depth spectroscopic examination, mainly including multiple 1D- and 2D-NMR and HRESIMS experiments and analyses. Cytotoxic activities of these compounds were evaluated against human liver cancer SK-hep-1 cell line by the MTT in vitro assay. Among them, compound 13 exhibited potent cytotoxic activity with IC₅₀ value of 38.18 μM, and compounds 7 and 8 showed moderate cytotoxic activities with IC₅₀ values of 58.11 and 54.61 μM, respectively.     

Generation of methylated violapyrones with improved anti-influenza A virus activity by heterologous expression of a type III PKS gene in a marine Streptomyces strain

Heterologous expression of the type III polyketide synthase (PKS) gene vioA in marine-derived Streptomyces youssoufiensis OUC6819 led to production of six violapyrones (VLPs), including four novel compounds VLPs Q–T (1–4) and two known compounds VLPs B and I (5 and 6). The structures of 1–4 were elucidated by a combination of spectroscopic analyses, including HR-ESIMS and 1D and 2D NMR data, demonstrating that 1–4 are novel VLPs which are methylated at 4-OH with their corresponding non-methylated counterparts to be VLP A, 5 and 6 and VLP C, respectively. Anti-influenza A [H1N1 (A/Virginia/ATCC1/2009) and H3N2 (A/Aichi/2/1968)] virus activity of compounds 1–6 as well as VLPs A and C were then evaluated using ribavirin as a positive control (IC₅₀?=?66.7 and 99.6?μM). The results revealed that these VLPs showed considerable anti-H1N1 and anti-H3N2 activities with IC₅₀ values of 30.6–132.4?μM and 45.3–150.0?μM, respectively. Notably, all the methylated VLPs displayed better anti-virus activity than their non-methylated counterparts, among which compound 3 (VLP S) exhibited the best activities. Interestingly, methylation at 4-OH has negative effect on the anti-MRSA (methicillin-resistant Staphylococcus aureus) activity instead, with methylated VLPs displaying decreased (2) or abolished (3 and 4) activities in comparison with each of their non-methylated counterparts.     

Bioactive cassane diterpenoids from the seeds of Caesalpinia sappan

Three new cassane-type diterpenoids named caesalppans G-I (1–3) together with three known ones (4–6), were isolated from the methanol extract of Caesalpinia sappan seeds. Their structures were determined based on spectroscopic data. Among the isolated compounds, compound 2 displayed a moderate antimalarial activity with an IC₅₀ value of 2.4 μM, and compound 4 showed mild anti-inflammatory activity with an IC₅₀ value of 28.65 μM.     

Trypanocidal and cytotoxic evaluation of synthesized thiosemicarbazones as potential drug leads against sleeping sickness

Thiosemicarbazones have become one of the promising compounds as new clinical candidates due to their wide spectrum of pharmaceutical activities. The wide range of their biological activities depends generally on their related aldehyde or ketone groups. Here, we report the pharmacological activities of some thiosemicarbazones synthesized in this work. Benzophenone and derivatives were used with N(4)-phenyl-3-thiosemicarbazide to synthesize corresponding five thiosemicarbazones (1–5). Their structures were characterized by spectrometrical methods analysis IR, NMR ¹H & ¹³C and MS. The compounds were then screened in vitro for their antiparasitic activity and toxicity on Trypanosoma brucei brucei and Artemia salina Leach respectively. The selectivity index of each compound was also determined. Four thiosemicarbazones such as 4, 2, 3 and 1 reveal interesting trypanocidal activities with their half inhibitory concentration (IC₅₀) equal to 2.76, 2.83, 3.86 and 8.48 μM respectively, while compound 5 (IC₅₀ = 12.16 μM) showed a moderate anti-trypanosomal activity on parasite. In toxicity test, except compound 1, which showed a half lethal concentration LC₅₀ >281 μM, the others exerted toxic effect on larvae with LC₅₀ of 5.56, 13.62, 14.55 and 42.50 μM respectively for thiosemicarbazones 4, 5, 3 and 2. In agreement to their selectivity index, which is greater than 1 (SI >1), these compounds clearly displayed significant selective pharmaceutical activities on the parasite tested. The thiosemicarbazones 2–5 that displayed significant anti-trypanosomal and cytoxicity activities are suggested to have anti-neoplastic and anti-cancer activities.     

Synthesis,bioactivity and molecular modeling studies on potential anti-Alzheimer piperidinehydrazide-hydrazones

A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ₄₂ self-aggregation inhibitory potentials, and antioxidant capacities, in vitro. All of the compounds displayed eeAChE and huAChE inhibitory activity in a range of IC₅₀ = 5.68–11.35 µM and IC₅₀ = 8.80–74.40 µM, respectively and most of the compounds exhibited good to moderate inhibitory activity on BuChE enzyme. Kinetic analysis and molecular modeling studies were also performed for the most potent compounds (1g and 1j). Not only the molecular modeling studies but also the kinetic analysis suggested that these compounds might be able to interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of the enzymes. In the light of the results, compound 1g and compound 1j may be suggested as lead compounds for multifunctional therapy of AD.     

Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy

MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1–E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC₅₀?=?2.80?μM for MMP-2 and IC₅₀?=?5.6?μM for MMP-8), compared to the positive drug CMT-1 (IC₅₀?=?1.29?μM). Compounds (E1–E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1–E18 may provide a research basis for the development of new agents against cancer.     

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.     

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.     

Anticomplement cycloartane triterpene glycosides from Beesia calthaefolia (Maxim.)

Investigation of the n-BuOH extract of the whole plant of Beesia calthaefolia led to the isolation of three new cycloartane triterpenoids (1–3) and two known compounds (4, 5). Their structures were elucidated by 1D and 2D NMR, HRESIMS and optical rotation spectral data. All of the isolates were investigated for their inhibitory effects on the classical pathway of the complement system. Among them, compound 3 showed stronger inhibitory activity (IC₅₀ 148.0 μM) than the positive control (rosmarinic acid, IC₅₀ 181.8 μM), while other compounds (1, 2, 4 and 5) showed moderate activity. The chemical compound studied in this article was rosmarinic acid (PubChem CID: 5281792).     

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).     

Novel phenolic and diterpenoid compounds isolated from the fruit spikes of Prunella vulgaris L. and their anti-inflammatory activities

Two novel phenolic compounds, prunellanate A (1) and prunellanate B (2), together with a diterpenoid compound, prunelladiterpenol A (3), were successfully isolated from the fruit spikes of Prunella vulgaris L. (Figure 1). Their structures were determined after extensive spectroscopic analyses including IR NMR, HR-ESI-MS empirical electronic circular dichroism (ECD), and X-ray diffraction. The biological activities of these new compounds on NO production in LPS (Lipopolysaccharide)-simulated RAW264.7 cells were evaluated. Compounds 1 and 3 showed significant anti-inflammatory activities revealing IC₅₀ values of 6.77 and 8.61 μM, respectively (aminoguanidine as positive control, IC₅₀ 20.33 ± 1.08 μM).     

Synthesis and bioevaluation of 6-chloropyridazin-3-yl hydrazones and 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines as cytotoxic agents

An efficient synthesis of a series of 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines is described via intramolecular oxidative cyclization of various 6-chloropyridazin-3-yl hydrazones with iodobenzene diacetate. The structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, NMR (¹H and ¹³C) and mass spectral data. All the thirty three compounds 3a-q and 4b-q synthesized in the present study were evaluated for their in vitro cytotoxic activities against two Acute Lymphoblastic Leukemia (ALL) cell lines named, SB-ALL and NALM-6, and a human breast adenocarcinoma cell lines (MCF-7). The results revealed that triazoles 4 exhibit better cytotoxicity than their hydrazone precursors 3. Among triazoles, compounds 4f, 4j and 4q exhibited potent cytotoxic activity against SB-ALL and NALM-6 with IC₅₀ values in the range of ∼1.64–5.66 μM and ∼1.14–3.7 μM, respectively, compared with doxorubicin (IC₅₀ = 0.167 μM, SB-ALL). Compounds 4f, 4j and 4q were subjected to apoptosis assay after 48 h treatment and these compounds induced apoptosis of NALM-6 cells via caspase 3/7 activation. Results revealed that compound 4q represents potential promising lead.     

Topoisomerase II inhibitors from the roots of Stellera chamaejasme L.

Three new compounds, including one daphnane diterpene (1), one sesquiterpene (6), and one lignan (7) have been isolated from the Stellera chamaejasme L., together with five other known compounds, including four daphnane diterpenenoids (2–5) and one lignan (8). The structures of the new compounds were elucidated by spectroscopic analysis. The cytotoxicities of compounds 1–8 towards human lung adenocarcinoma cells (A549 cells) were evaluated using a sulforhodamine B assay. All of the compounds displayed significant cytotoxicity, with IC₅₀ values in the ranging of 0.2 nM to 2.0 μM. Mechanistic studies revealed that the antitumor activities of compounds 1–3 and 7 were derived from their inhibition of topoisomerase II (Topo II). Furthermore, as a Topo II inhibitor, compound 1 was found to effectively induced G2-M phase cell cycle arrest and apoptosis in cancer cells.     

Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as Aurora kinase inhibitors

A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC₅₀ values in range of 2.2–4.6?μM, while the IC₅₀ value of reference compound VX-680 was 8.5–15.3?μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC₅₀ values were 118?±?8.1 and 80?±?4.2?nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.     

Discovery of 4-functionalized phenyl-O-β-d-glycosides as a new class of mushroom tyrosinase inhibitors

A series of 4-functionalized phenyl-O-β-d-glycosides were designed, synthesized and evaluated as a new class of mushroom tyrosinase inhibitors. The results demonstrated that compounds 6a–13a bearing a thiosemicarbazide moiety exhibited potent activities with IC₅₀ values range from 0.31 to 52.8 μM. Particularly, compound 9a containing acetylated glucose moiety was found to be the most active molecule with an IC₅₀ value of 0.31 μM. SARs analysis suggested that (1) the thiosemicarbazide moiety remarkably contributed to the increase of inhibitory effects on tyrosinase; (2) the configuration and bond type of sugar moiety also played a very important role in determining their inhibitory activities. The inhibition kinetics and inhibition mechanism study revealed that compound 9a was reversible and competitive type inhibitor, whereas compound 13a was reversible and competitive–uncompetitive mixed-II type inhibitor.     

Chalcone derivatives bearing chromen or benzo[f]chromen moieties: Design,synthesis, and evaluations of anti-inflammatory,analgesic, selective COX-2 inhibitory activities

Thirty-eight chalcone derivatives bearing a chromen or benzo[f]chromen moiety were synthesized and evaluated for their anti-inflammatory and analgesic activities. Using an ear edema model, anti-inflammatory activities were observed for compounds 3a-3s (ear inflammation: 1.75–3.71 mg) and 4a-4s (ear inflammation: 1.71–4.94 mg). All compounds also displayed analgesic effects with inhibition values of 66.7–100% (3a-3s) and 96.2–100% (4a-4s). The 12 compounds that displayed excellent anti-inflammatory and analgesic effects were tested for their inhibitory activity against ovine COX-1 and COX-2. Six compounds bearing a chromen moiety were weak inhibitors of the COX-1 isozyme but showed moderate COX-2 isozyme inhibitory effects (IC₅₀s from 0.37 μM to 0.83 μM) and COX-2 selectivity indexes (SI: 22.49–9.34). Those bearing a benzo[f]chromen moiety were more selective toward COX-2 than those bearing a chromen moiety with IC₅₀s from 0.25 μM to 0.43 μM and COX-2 selectivity indexes from SI: 31.08 to 20.67.     

Does conjugation of antioxidants improve their antioxidative/anti-inflammatory potential?

A series of symmetric and asymmetric spermine (SPM) conjugates with all-trans-retinoic acid (ATRA), acitretin (ACI), (E)-3-(trioxsalen-4′-yl)acrylic acid (TRAA) and l-DOPA, amides of ACI, l-DOPA and TRAA with 1-aminobutane, benzylamine, dopamine and 1,12-diaminobutane as well as hybrid conjugates of O,O′-dimethylcaffeic acid (DMCA) with TRAA or N-fumaroyl-indole-3-carboxanilide (FICA) and 2-(2-aminoethoxy)ethanol were synthesized and their antioxidant properties were studied. The reducing activity (RA)% of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay and found to be in the range 0–92(20 min)%/96(60 min)% at 100 μM, the most powerful being the conjugates l-DOPA-SPM-l-DOPA (8, RA = 89%/96%) and l-DOPA-dopamine (13, RA = 92%/92%). Conjugate DMCA-NH(CH₂CH₂O)₂-FICA (14) was the most powerful LOX inhibitor with IC₅₀ 33.5 μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5 μM), ACI-SPM-TRAA (7, IC₅₀ 41.5 μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65 μM), 13 (IC₅₀ 81.5 μM) and ACI-dopamine (11, IC₅₀ 87 μM). The most potent inhibitors of lipid peroxidation at 100 μM were the conjugates 15 (98%) and ACI-SPM-ACI (4, 97%) whereas all other compounds showed activities comparable or lower than trolox. The most interesting compounds, namely ATRA-SPM-ATRA (3), 4, 10, 11 and 15, as well as unconjugated compounds such as ATRA and dopamine, were studied for their anti-inflammatory activity in vivo on rat paw oedema induced by Carrageenan and found to exhibit, for doses of 0.01 mmol/mL of conjugates per Kg of rat body weight, weaker anti-inflammatory activities (3.6–40%) than indomethacin (47%) with conjugate 3 being the most potent (40%) in this series of compounds. The cytocompatibility of selected compounds was evaluated by the viability of RAMEC cells in the presence of different concentrations (0.5–50 μM) of the compounds. Conjugates 3 (IC₅₀ 2.6 μM) and 4 (IC₅₀ 4.7 μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3 μM) and ACI (IC₅₀ 14.6 μM), whereas conjugate 15 (IC₅₀ 12.9 μM) was less cytotoxic than either DCSP (IC₅₀ 11.3 μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9 μM).