Hybrid pharmacophore design and synthesis of donepezil-inspired aurone derivative salts as multifunctional acetylcholinesterase inhibitors.

Flavonoids, a ubiquitous group of plant polyphenols, are well-known for their beneficial effects on human health. Their phenylchromane skeletons have structural similarities to donepezil [the US FDA-approved drug used to treat Alzheimer's disease (AD)]. The objective of this study was to design and synthesize valuable agents derived from flavonoids for relieving the symptoms of AD. A variety of flavonoid derivative salts incorporating benzylpyridinium units were synthesized and several of them remarkedly inhibited acetylcholinesterase (AChE) activity in vitro. Additionally, aurone derivative salts protected against cell death resulting from t-BHP exposure in rat pheochromocytoma PC12 cells and slightly promoted neurite outgrowth. Furthermore, they potently suppressed the aggregation of amyloid-ß (Aß1-42). Our findings highlight the effectiveness of donepezil-inspired aurone derivative salts as multipotent candidates for AD.

Synthesis of raloxifene-like quinoxaline derivatives by intramolecular electrophilic cyclization with disulfides.

The intramolecular electrophilic cyclization of alkynes with disulfides to form thieno[2,3-b]quinoxaline structures and to introduce thioether substituents afforded quinoxaline derivatives (7a-7d, 8a-8d). Among obtained eight derivatives, the raloxifene analogues (7c, 8b) showed specifically high cytotoxicity against breast cancer cells (SK-BR-3), and raloxifene analogues (8a) showed the highest cytotoxicity against human leukemia cells (HL-60). None of the raloxifene analogues (7a-7d, 8a-8d) showed cytotoxicity against human lung fibroblasts (WI-38), which are normal cells.

Promotion of ABCG2 gene expression by neolignans from Piper longum L.

We focused on Piper longum L., a herbal drug produced in Myanmar, which has a renoprotective effect. Thus, we attempted to isolate and identify compounds that enhance the expression of the ABCG2 gene from the aerial parts of the plant except for the fruit. Among the various P. longum extracts, we isolated and identified the components. Using Caco-2 cells, the hABCG2 mRNA expression-enhancing effects of the isolated compounds were compared with the positive reference compound (3-methylcholanthrene [3MC]) using real-time polymerase chain reaction. Six compounds were isolated and identified from the methanol extract of P. longum. Among the isolated compounds, licarin A and neopomatene had lower toxicity and higher hABCG2 mRNA expression-enhancing effects in Caco-2 cells. Suppression of hAhR expression by siRNA reduced the activity of licarin A and neopomatene, as well as the hAhR agonist 3MC, suggesting that these 2 compounds may act as hAhR agonists to promote hABCG2 expression.

Comparative analysis of p-terphenylquinone and seriniquinone derivatives as reactive oxygen species-modulating agents.

Quinones are widespread in plants, animals, insects, and microorganisms. Several anticancer agents contain quinone structures as critical parts to show remarkable potential and distinctive modes of actions. The purpose of this study was to investigate the structure-activity relationships of microbial quinones and their derivatives as anticancer agents. A series of p-terphenylquinone and seriniquinone derivatives were therefore prepared. Treatment of the synthesized quinones possessed antiproliferative activity on human leukemia HL-60 cells in a dose-dependent fashion. In addition, seriniquinone derivatives elevated cellular reactive oxygen species (ROS) levels, thereby triggering the ensuing apoptotic events. Our findings emphasize the excellent potential of seriniquinone derivatives as redox cycling-induced ROS-modulating anticancer agents.

α-Glucosidase Inhibitors from the Stems of Knema globularia.

Six new compounds, globunones A-F (1-6), and two new flavonoids (7 and 8) together with nine known compounds (9-17) were isolated from the stems of Knema globularia. The chemical structures of 1-8 were elucidated by an analysis of their NMR and high-resolution electrospray ionization mass spectrometry data as well as by comparison with literature values. The absolute configurations were determined using time-dependent density functional theory electronic circular dichroism (TD-DFT-ECD). Globunones A-E (1-5) represent the initial combined structures of a flavan-3-ol core and a 1,4-benzoquinone core. Globunone F (6) is the first flavanone-type compound bearing a 2-(2,4-dihydroxyphenyl)-2-oxoethyl group found to date in Nature. Compounds 1-3 and 6-17 were tested for their yeast α-glucosidase inhibitory activity. All compounds tested (except for 13 and 14) showed potent inhibition toward α-glucosidase with IC50 values in the range 0.4-26.6 µM. Calodenin A (15) was the most active compound with an IC50 value of 0.4 µM (the positive control, acarbose, IC50 93.6 µM). A kinetic analysis of 15 revealed that it is a noncompetitive inhibitor with a Ki value of 3.4 µM.

Effect of Compounds from Moringa oleifera Lam. on in Vitro Non-Alcoholic Fatty Liver Disease (NAFLD) Model System.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in the world, with a prevalence of 25 % in many countries. To date, no drug has been approved to treat NAFLD, therefore, the use of phytochemicals to prevent this disease is meaningful. In this study, we focused on the effects of Moringa oleifera Lam. on diabetes, attempted to isolate compounds that regulate NAFLD. Compounds 1 and 2 were isolated from the ethyl acetate fraction of M. oleifera. Spectral data revealed that they were 1-hydroxy-3-phenylpropan-2-yl benzoate (1) and benzyl benzylcarbamate (2), respectively. The three-dimensional structure of compound 1 was determined by single crystal X-ray structural analysis. Neither compound was toxic to HepG2 cells, and compound 1 was found to have a concentration-dependent inhibitory effect on intracellular lipid accumulation induced by stimulation of linoleic acid (LA). As a result of measuring the effects of compound 1 on the intracellular lipid production-related protein, it was found that compound 1 enhanced protein expression that promotes lipolysis. On the other hand, since the action of compound 1 was similar to that of PPARα agonists, it is deduced that compound 1 enhanced the activity of PPARα and further enhanced the expression of lipolytic proteins, which is related to the suppression of intracellular lipid accumulation. Furthermore, as the result of docking simulation, compound 1 had a higher binding affinity to the ligand binding site of PPARα than fenofibrate, which is a PPARα agonist, and thus compound 1 was considered to be promising as an agonist of PPARα.

Synthesis and photophysical properties of selenopheno[2,3-b]quinoxaline and selenopheno[2,3-b]pyrazine heteroacenes.

In this paper, we report the novel synthesis of three different heterocycles, namely 2-arylselenopheno[2,3-b]quinoxaline, 3-(aryl/alkylselanyl)-2-arylselenopheno[2,3-b]quinoxaline and 6-phenyl-7-(arylselanyl)selenopheno[2,3-b]pyrazine derivatives, from the corresponding 2,3-dichloroquinoxaline and 2,3-dichloropyrazine derivatives. Furthermore, photophysical properties were investigated to study the effect of heteroatoms on UV-absorbance and fluorescence properties.

In situ air oxidation and photophysical studies of isoquinoline-fused N-heteroacenes.

An efficient, metal free and environment friendly synthesis of isoquinoline-fused benzimidazole has been developed via in situ air oxidation. Also, syntheses of isoquinoline-fused quinazolinone heteroacenes were successfully achieved. The synthesized isoquinoline-fused benzimidazole and isoquinoline-fused quinazolinone derivatives showed λmax, Fmax and Φf values in the ranges 356-394 nm, 403-444 nm and 0.063-0.471, respectively, in CHCl3.

Design and synthesis of quinoxaline-1,3,4-oxadiazole hybrid derivatives as potent inhibitors of the anti-apoptotic Bcl-2 protein.

Quinoxaline is one of the privileged heterocyclic fragments for drug molecules. Quinoxaline anticancer drug candidates XK469 and CQS exhibit antiproliferative and proapoptotic properties against various cancers. Based on their chemical structures, we therefore synthesized a series of quinoxaline-1,3,4-oxadiazole hybrids and assessed their anticancer potential on human leukemia HL-60 cells. Although these hybrids exerted significant inhibition of HL-60 cell proliferation, they showed high cytotoxicity on human normal cells (WI-38). Utilizing information from molecular modelling of the hybrids to the anti-apoptotic Bcl-2 protein, we added substructures including phenyl, piperazine, piperidine, and morpholine rings to their frameworks. The designed quinoxaline-1,3,4-oxadiazole hybrid derivatives successfully induced apoptotic response on HL-60 cells with low toxicity on WI-38 cells. Furthermore, RT-PCR analysis demonstrated that these derivatives predominantly inhibit Bcl-2 expression. Our findings highlight the great potential for the development of synthetic quinoxaline-1,3,4-oxadiazole hybrid derivatives as proapoptotic anticancer agents.

Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as potent antiproliferative agents via a hybrid pharmacophore approach.

Imiquimod (1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine) is efficacious in topical therapy for certain types of skin cancers. Structurally similar EAPB0203 (N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine) has been shown higher in vitro potency than imiquimod. Besides, triazole, oxadiazole, and thiadiazole rings are privileged building blocks in drug design. A series of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole and [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-thiadiazole derivatives were therefore synthesized by incorporation of these rings into the structure of EAPB0203 and assessed their antiproliferative effects against various cancer cell lines. The 1,3,4-oxadiazole derivatives demonstrated the superior effectiveness compared to imiquimod and EAPB0203. Our findings highlight the excellent potential of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as anticancer agents.

Comparative analysis of stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors with neuroprotective and anti-inflammatory activities.

Stilbenes and benzofuran neolignans are important groups of plant phenolics therefore they play a significant role in plants and human health. The objective of this study was to investigate the structure-activity relationships of naturally occurring stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors. A series of these compounds were prepared and assessed for their inhibition on acetylcholinesterase activity. δ-Viniferin, pterostilbene trans-dehydrodimer, pallidol, grossamide, and boehmenan exerted acetylcholinesterase inhibitory potential. The several oligomeric compounds protected against cell damage resulting from t-BHP exposure and inhibited lipopolysaccharide/interferon-gamma (LPS/IFNγ)-induced NO production in vitro. Our findings highlight the great potential of pterostilbene trans-dehydrodimer, pallidol, and boehmenan as multifunctional nutraceuticals for management of neurodegenerative diseases.

Synthesis of carbazoloquinone derivatives and their antileukemic activity via modulating cellular reactive oxygen species.

Carbazoloquinone alkaloids are of great interest as privileged structures for anticancer drug molecules. The purpose of this study was to investigate the structure-activity relationships of carbazoloquinone derivatives as anticancer agents. A series of carbazoloquinones including murrayaquinone A, koeniginequinones A and B, and related analogues were therefore prepared. Palladium-catalyzed intramolecular cyclization reaction mechanism was well elucidated by DFT calculations. Treatment of the synthesized derivatives showed cytotoxicity on human leukemia HL-60 cells in a dose-dependent fashion. In addition, murrayaquinone A and ß-brazanquinone elevated cellular levels of reactive oxygen species (ROS), thereby triggering apoptosis. Our findings emphasize the excellent potential of carbazoloquinone derivatives as ROS-inducing anticancer agents.

Sentulic acid isolated from Sandoricum koetjape Merr attenuates lipopolysaccharide and interferon gamma co-stimulated nitric oxide production in murine macrophage RAW264 cells.

A seco-triterpenoid, sentulic acid (SA) isolated from Sandoricum koetjape Merr attenuated nitric oxide (NO) production following co-stimulation with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in RAW264.7 macrophage cells. The mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IFNγ, interleukin (IL)-6, and IL-12 in LPS/IFNγ co-stimulated RAW264.7 cells also decreased upon SA treatment. To determine the molecular mechanisms underlying the inhibitory effect of SA on LPS/IFNγ-induced NO production in RAW264.7 cells, we further analyzed Toll-like receptor (TLR) signaling by western blotting. The expression of TLR4 and IFN signaling molecules in cells treated with SA was significantly suppressed compared to that in cells not treated with SA. Additionally, SA inhibited the binding of LPS to the TLR4 receptor in RAW264.7 cells stimulated with Alexa Fluor 488-conjugated LPS. These results demonstrate that SA attenuates NO production after LPS/IFNγ co-stimulation in RAW264.7 cells by inhibiting the binding of LPS to TLR4. Our findings suggest that SA is beneficial for the treatment of inflammatory diseases.

Synthesis and antimicrobial activity of ß-carboline derivatives with N2-alkyl modifications.

ß-Carbolines constitute a vast group of indole alkaloids and exhibit various biological actions. The objective of this study was to investigate the structure-activity relationships of ß-carboline derivatives on in vitro inhibitory effects against clinically relevant microorganisms. A series of ß-carboline dimers and their N2-alkylated analogues were therefore prepared and evaluated for their antimicrobial effects. Among these, a dimeric 6-chlorocarboline N2-benzylated salt exerted potent activity against Staphylococcus aureus at MICs of 0.01-0.05 µmol/mL. Our work highlights that N1-N1 dimerization and N2-benzylation significantly enhanced the antimicrobial effects of compounds.

Synthesis of coumarin derivatives and their cytoprotective effects on t-BHP-induced oxidative damage in HepG2 cells.

Coumarins are ubiquitous in higher plants and exhibit various biological actions. The aim of this study was to investigate the structure-activity relationships of coumarin derivatives on tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human hepatoma HepG2 cells. A series of coumarin derivatives were prepared and assessed for their cytoprotective effects. Among these, a caffeoyl acid-conjugated dihydropyranocoumarin derivative, caffeoyllomatin, efficiently protected against cell damage elicited by t-BHP. Our findings suggest that caffeoyllomatin appears to be a potent cytoprotective agent.

Effects of Flavonoids and Triterpene Analogues from Leaves of Eleutherococcus sieboldianus (Makino) Koidz. 'Himeukogi' in 3T3-L1 Preadipocytes.

Eleutherococcus sieboldianus (Makino) Koidz. is a local product from the area in and around Yonezawa City in Yamagata Prefecture, Japan. It has been used as a medicinal plant for a long time. We isolated and identified four types of flavonoid glycosides [astragalin (1), isoquercetin (2), rhamnocitrin 3-O-glucoside (3), and nicotiflorin (4)], a triterpene [methyl hederagenin (5)], and three types of triterpene glycosides [δ-hederin (6), echinocystic acid 3-O-arabinoside (7), and cauloside B (8)] from the methanol extract of E. sieboldianus, which regulates lipid accumulation in 3T3-L1 preadipocytes. Among the compounds isolated, 2 and 8 up- and down-regulated lipid accumulation and insulin induced adipocyte differentiation in 3T3-L1 preadipocytes. Compound 2 induced up-regulation of lipid accumulation and decreased adipocyte size, while 8 down-regulated lipid accumulations without decreasing cell size. Additionally, 2 increased adipogenic proteins [peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty-acid-binding protein 4 (FABP4)]. In contrast, 8 decreased the levels of all adipogenic proteins and glucose transporter type 4 (GLUT4), but increased adiponectin.

Suppression of EC-SOD by oxLDL During Vascular Smooth Muscle Cell Proliferation.

Reactive oxygen species (ROS) produced by endothelial cells and macrophages play important roles in atherogenesis because they promote the formation of oxidized low-density lipoproteins (oxLDL). Extracellular-superoxide dismutase (EC-SOD) is mainly produced by vascular smooth muscle cells (VSMCs), is secreted into the extracellular space, and protects cells from the damaging effects of the superoxide anion. Thus, the expression of EC-SOD in VSMCs is crucial for protecting cells against atherogenesis; however, oxLDL-induced changes in the expression of EC-SOD in VSMCs have not yet been examined. We herein showed that oxLDL decreased EC-SOD mRNA and protein levels by binding to lectin-like oxidized LDL receptor-1 (LOX-1). Moreover, we demonstrated the significant role of mitogen-activated protein kinase (MEK)/extracellular-regulated protein kinase (ERK) signaling in oxLDL-elicited reductions in the expression of EC-SOD and proliferation of VSMCs. The results obtained with the FCS treatment indicate that oxLDL-elicited reductions in the expression of EC-SOD are related to the proliferation of VSMCs. We herein showed for the first time that luteolin, a natural product, restored oxLDL-induced decreases in the expression of EC-SOD and proliferation of VSMCs. Collectively, the results of the present study suggest that oxLDL accelerates the development of atherosclerosis by suppressing the expression of EC-SOD and also that luteolin has potential as a treatment for atherosclerosis. J. Cell. Biochem. 117: 2496-2505, 2016. © 2016 Wiley Periodicals, Inc.

Flavonoid profile and antileukemic activity of Coreopsis lanceolata flowers.

Coreopsis lanceolata is a perennial plant belonging to the Asteraceae family. In this study, flavonoid profile and antileukemic potential of yellow flowers of the plant were investigated. The total flavonoid content in EtOAc fraction of the flower methanol extract was found to be 420mg/g and showed the inhibition of cell proliferation and possible induction of apoptosis in human leukemia HL-60 cells. Our phytochemical research led to the isolation of rare flavonoids including a flavanone, chalcones, and aurones; in particular, 4-methoxylanceoletin demonstrated the potent antiproliferative activity. Comparison with other Asteraceaeous flowers by UPLC-MS analysis indicated that the isolates are characteristic constituents of C. lanceolata.

Antileukemic activity of lignans and phenylpropanoids of Cinnamomum parthenoxylon.

In this study, we evaluated the in vitro cytotoxicity of fractions and isolated constituents from Cinnamomum parthenoxylon woods against human leukemia HL-60 and U937 cells. The n-Hex, EtOAc, and MeOH-H2O fractions of the woods inhibited cell proliferation in both cell lines. Our phytochemical investigation of the n-Hex and EtOAc fractions led to the isolation of lignans and phenylpropanoids, whose chemical structures were confirmed by spectroscopic analyses. All isolated compounds were evaluated for their in vitro antileukemic activity; especially, hinokinin and cubebin exhibited strong inhibition toward U937 cell proliferation. Morphological observation indicated that these cytotoxic actions were mediated by apoptosis. Our findings suggested that an oxygenated functional group at the C-9 position in dibenzylfuran skeleton contributed their potency. In addition, these results enhanced the ethnopharmacological value of C. parthenoxylon.

Effects of Functional Groups and Sugar Composition of Quercetin Derivatives on Their Radical Scavenging Properties.

Quercetin derivatives are widespread in the plant kingdom and exhibit various biological actions. The aim of this study was to investigate the structure-activity relationships of quercetin derivatives, with a focus on the influence of functional groups and sugar composition on their antioxidant capacity. A series of quercetin derivatives were therefore prepared and assessed for their DPPH radical scavenging properties. Isoquercetin O-gallates were more potent radical scavengers than quercetin. The systematic analysis highlights the importance of the distribution of hydroxy substituents in isoquercetin O-gallates to their potency.