Desmoarylcoumarin and episoyasapogenol B: two new compounds from Desmodium salicifolium (Poir.) DC (Fabaceae).

A new 3-arylcoumarin, 7-hydroxy-6-(1,1-dimethylallyl)-2',5'-dihydroxy-4'-(3,3dimethylprenyl)-3-arylcoumarin (desmoarylcoumarin) 1, a previously unreported oleanane-type triterpenoid, 3ß,22ß,23-trihydroxyolean-12-en (episoyasapogenol B) 2, together with five known flavonoids including darbergioidin (3), isoferreirin (4), quercetin (5), vitexin (6), swertizin (7), and one carbohydrate, sucrose (8) were isolated from the methanolic extract of the roots of Desmodium salicifolium. Their structures were elucidated mainly by extensive spectroscopic analysis (1D and 2D) and mass spectrometric (HRFAB-MS) data. The methanolic extract, EtOAc and n-BuOH fractions as well as some isolated compounds were assessed for their antibacterial and antioxidant activities. The EtOAc fraction exhibited moderate activity against Enterococcus faecalis with MIC value of 128 µg/mL. The methanolic extract and the EtOAc fraction displayed DPPH scavenging activity with EC50 values of 5.99 and 2.06 µg/mL, respectively. Compound 1 showed a moderate antibacterial activity against Enterococcus faecalis with a MIC of 16 µg/mL. It also showed moderate DPPH scavenging activity.

3-Arylcoumarin inhibits vascular calcification by inhibiting the generation of AGEs and anti-oxidative stress.

OBJECTIVE: This work aims to screen drugs for preventing and treating vascular calcification. Method: We screened a series of 3-arylcoumarins for the detection of vascular calcification-associated factors using human aortic vascular smooth muscle cells. RESULTS: We found that compounds 14 and 32 significantly inhibited alkaline phosphatase (ALP) activity similar to aminoguanidine hydrochloride (AGH) in a cellular model of AGEs-induced calcification. We also found that compounds 14 and 32 could significantly decrease the levels of factors such as AGEs, intracellular calcium ions, and total ROS in the calcified cell model. Further study indicates that compound 14 could significantly inhibit the expression of P-ERK1/2, PKC, NF-κB, RAGE and OPN proteins and increased the expression of SM22-α and PPAR-γ proteins in the calcified cells. CONCLUSION: We speculate that compound 14 inhibits vascular calcification by inhibiting oxidative stress and inhibiting AGEs production, suggesting that 3-arylcoumarin derivatives are potential candidates for the treatment of vascular calcification.

Vascular calcification is a process similar to bone formation, which is highly adjustable and active. Currently, there are no specific drugs to delay or reverse vascular calcification. Through the screening of 44 coumarin compounds synthesised by our group, compound 14 was obtained to dose-dependently inhibit the calcification of vascular smooth muscle cells without affecting the normal proliferation of cells, decreasing the intracellular calcium concentration, inhibiting the activity of ALP enzyme. In conclusion, the calcium lowering effect of compound 14 is a potential candidate for drugs for the treatment of vascular calcification.

Natural source, bioactivity and synthesis of 3-Arylcoumarin derivatives.

3-arylcoumarins with different pharmacological properties widely exist in a variety of natural plants. The extensive research on 3-arylcoumarins was attributed to its therapeutic and relatively easy isolation. Therefore, 3-arylcoumarins can be recognised as useful structures for the design of novel compounds with potential pharmacological interest, particularly in the fields of anti-inflammatory, anti-cancer, antioxidant, Monoamine oxidase (MAO) enzyme inhibition, etc. The current review highlights the biological activities, design, and chemical synthetic methods of 3-arylcoumarins derivatives as well as their important natural product sources.

Mechanism of 3-arylcoumarin derivatives inhibiting vascular calcification / 中国药科大学学报

@#To reveal the pharmacological mechanism of 3-arylcoumarin derivative 3-(4′-hydroxyphenyl)-6-hydroxycoumarin (SJ-6) against vascular calcification, advanced glycation end products (AGEs) were used to induce the calcification of human aortic vascular smooth muscle cells (HCASMCs), and calcification was identified by alizarin red staining and quantification.The effects of SJ-6 on alkaline phosphatase (ALP) activity, cell proliferation rate, calcium content, and total reactive oxygen species (ROS), superoxide dismutase (SOD), AGEs, and tetra methylethlene diamine proteinase factor-α (TNF-α), interleukin-6 (1L-6), interleukin-β (1L-β), runt-related transcription factor 2 mRNA (Runx2 mRNA), the receptor of advanced glycation endproducts (RAGE), nuclear factor kappa-B (NF-κB), napdh oxidase-1 (NoX-1), protein kinase C(PKC), protein kinase b(AKT), p38 mitogen-activated protein kinase (p38 MAPK), and smooth muscle actin-α (SMA-α) protein expression were determined.According to our results, SJ-6 significantly decreased AGEs content, ALP activity, intracellular calcium content, ROS content, Runx2 mRNA and inflammatory factors TNF-α, 1L-6 and 1L-β (P < 0.05) and increased SOD content (P < 0.01), with similar to those of the positive control drug aminoguanidine hydrochloride (AGH).Therefore, we investigated the pharmacological mechanism of compound SJ-6, which was found to significantly inhibit the expression of RAGE, NF-κB, NoX-1, PKC, Akt, p-p38 and other essential signaling proteins in the calcified cell model (P < 0.01) and increas the expression of smooth actin SMA-α (P < 0.01).SJ-6 inhibits vascular calcification by inhibiting oxidative stress and the expression of AGEs/RAGE, Akt/PKC and NF-κB signaling pathways, suggesting that it may be a novel drug for the treatment of vascular calcification.

Synthesis of 3-aryl-4-(N-aryl)aminocoumarins via photoredox arylation and the evaluation of their biological activity.

A new series of 3-aryl-4-(N-aryl)aminocoumarins was synthesized in two steps starting from the natural product 4-hydroxycoumarin using the photoredox catalysis for the key step. These conditions reactions allowed to make CC bonds is up to 95% yields in mild conditions, easy operation, in an environmentally benign way, and are compatible with several patterns of substitution. The biological activity of the new compounds was tested in vitro against MCF-7, MDA-MB-231, and CCD-1072Sk cancer cell lines, as soon as to promastigotes and intracellular amastigotes of Leishmania amazonensis. Compounds 17d, 17s and 17x showed activity against promastigote forms (IC50 = 5.96 ± 3.210, 9.05 ± 2.855 and 5.65 ± 2.078 µM respectively), and compound 17x presented the best activity against L. amazonensis amastigote intracellular form (IC50 = 9.6 ± 1.148 µM), no BALB/c peritoneal macrophage cytotoxicity at assayed concentrations (CC50 > 600 µM), and high selectivity to parasites over the mammalian cells (Selectivity Index > 62.2). There was no expressive activity for the cancer cell lines. Single crystal X-ray diffraction analysis was employed for structural elucidation of compounds 17a and 17s. In silico analyses of physicochemical, pharmacokinetic, and toxicological properties suggest that compound 17x is a potential candidate for anti-leishmaniasis drugs.

Two new compounds with Nrf2 inducing activity from Glycyrrhiza uralensis.

Two new compounds including a new 3-arylcoumarin liquiritcoumarin (1), and a new flavonoid glycoside crotoliquiritin (2), together with twelve known compounds (3-14) were isolated from the radix and rhizome of Glycyrrhiza uralensis. Their structures were elucidated on the basis of extensive spectroscopic data analyses. All of the compounds were evaluated for the cytotoxic activities. Only compound 5 showed moderate effects with IC50 of 11.46 µM for A549 cells and IC50 of 7.38 µM for NCI-H292 cells. Compounds 1 and 2 were demonstrated to be Nrf2 pathway activators by using a stable antioxidant response element (ARE)-dependent reporter gene assay together with immunoblot and immunofluorescence analysis.

Identification of 7,8-dihydroxy-3-phenylcoumarin as a reversible monoamine oxidase enzyme inhibitor.

We herein report the biological evaluation of 3-arylcoumarin derivatives (3a-l) as potential human monoamine oxidase-A and -B (hMAO-A and hMAO-B) inhibitors. The result indicated that 7,8-dihydroxy-3-(4-nitrophenyl)coumarin (3j) was most effective against MAO-A (inhibition concentration [IC50 ] = 6.46 ± 0.02 µM) and MAO-B (IC50 = 3.8 ± 0.3 µM) enzymes than other synthesized compounds and reference compounds (pargyline and moclobemide). Furthermore, compound (3j) showed (a) nonselectivity against hMAO enzymes, (b) reversible hMAO enzymes inhibition, and (c) neuroprotection against H2 O2 -treated human neuroblastoma (N2a) cells. Finally, a molecular modeling study revealed that the hMAO enzymes inhibitory activity of the compound (3j) may be due to the orientation where the nitro (NO2 ) group lies deep into the receptor and the phenyl ring directed toward flavin adenosine dinucleotide via hydrogen bond interaction, and possible π-π interaction with various important residues. Thus, the results of the present study demonstrate that compound (3j) can be considered as a promising scaffold for the development of hMAO-A and hMAO-B inhibitors.

Synthesis and biological evaluation of 3-arylcoumarins as potential anti-Alzheimer's disease agents.

Alzheimer's disease, a neurodegenerative illness, has the extremely complex pathogenesis. Accumulating evidence indicates there is a close relationship between several enzymes and Alzheimer's disease. Various substituted 3-arylcoumarin derivatives were synthesised, and their in vitro activity, including cholinesterase inhibitory activity, monoamine oxidase inhibitory activity, and antioxidant activity were investigated. Most of the compounds exhibited high activity; therefore 3-arylcoumarin compounds have the potential as drug candidates for the treatment of Alzheimer's disease.

Synthesis and biological evaluation of 3-arylcoumarin derivatives as potential anti-diabetic agents.

A variety of substituted 3-arylcoumarin derivatives were synthesised through microwave radiation heating. The method has characteristics of environmental friendliness, economy, simple separation, and purification process, less by-products and high reaction yield. Those 3-arylcoumarin derivatives were screened for antioxidant, α-glucosidase inhibitory and advanced glycation end-products (AGEs) formation inhibitory. Most compounds exhibited significant antioxidant and AGEs formation inhibitory activities. Anti-diabetic activity studies showed that compounds 11 and 17 were equipotent to the standard drug glibenclamide in vivo. According to the experimental results, the target compound 35 can be used as a lead compound for the development of new anti-diabetic drugs. The whole experiment showed that anti-diabetic activity is prevalent in 3-arylcoumarins, which added a new natural skeleton to the development of anti-diabetic active drugs.

Identification of 7,8-Diacetoxy-3-Arylcoumarin Derivative as a Selective Cytotoxic and Apoptosis-inducing Agent in a Human Prostate Cancer Cell Line.

BACKGROUND/AIM: Coumarins are a member of the benzopyrone family of compounds with diverse and interesting pharmacological properties. In the present study, we report the in vitro cytotoxicity evaluation of 7,8-Diacetoxy-3-arylcoumarin derivatives (5a-h) in human prostate (PC-3) and breast (MDA-MB-231) cancer cell lines. MATERIALS AND METHODS: The cytotoxic activity was evaluated using crystal violet dye-binding assay. Furthermore, the most active compound in vitro cytotoxic activity in human non-cancerous cell line and its effect on the cell-cycle phases, apoptosis proteins expression, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and Glutathione (GSH) level were performed. RESULTS: Among the eight compounds that were evaluated, 7,8-Diacetoxy-3-(4-methylsulfonyl phenyl)coumarin (5f) was the most active derivative with highest cytotoxic activity and selectivity against the PC-3 cell line vs. the non-cancerous WPE1-N22 cell line. The cytotoxic action of compound 5f in PC-3 cells is associated with the cell-cycle arrest at -G0/G1 phase, apoptosis, loss in mitochondrial membrane potential (MMP), induced reactive oxygen species (ROS) production and depletion of Glutathione (GSH) level. CONCLUSION: The result indicates that the presence of p-methylsulfonylphenyl group on compound 5f is critical in modulating selective cytotoxic activity and induction of apoptosis via the mitochondrial apoptotic signaling pathway that is independent of cytochrome c release.

In Vitro Inhibition of Human Placental Glutathione S-Transferase by 3-Arylcoumarin Derivatives.

Glutathione S-transferases (EC: 2.5.1.18, GSTs) are phase II detoxification enzymes that catalyze the conjugation of various electrophilic compounds to glutathione (GSH), thus usually producing less reactive and more water soluble compounds. However, there is evidence that elevated expression of GSTs, especially GSTP1, is involved in the resistance of tumor cells against chemotherapeutic agents. In this study, we synthesized and investigated the inhibitory effects of differently substituted 3-arylcoumarin derivatives on human placental GST, identified as GSTP1-1, using 1-chloro-2,4-dinitrobenzene as a substrate. A known potent inhibitor of GST, ethacrynic acid was used as a positive control. Among the tested compounds, 6,7-dihydroxy substituted coumarin derivatives exhibited the highest inhibitory activity (IC50 = 13.50-20.83 µM). These results suggest that 6,7-dihydroxy-3-arylcoumarins may represent a new promising scaffold to discover potent GST inhibitors.

In vitro evaluation of 3-arylcoumarin derivatives in A549 cell line.

UNLABELLED: Coumarins are naturally-occurring compounds with diverse and interesting biological activities. In the present study, we evaluated the in vitro cytotoxic effect of 8-(acetyloxy)-3-[4-(acetyloxy)phenyl]-2-oxo-2H-chromen-7-yl acetate (6); 8-(acetyloxy)-3-(4-methanesulfonyl phenyl)-2-oxo-2H-chromen-7-yl acetate (7); 4-(2-oxo-2H-chromen-3-yl)phenyl acetate (8); 3-(4-methanesulfonylphenyl)-2H-chromen-2-one (9); 4-(4-methyl-2-oxo-2H-chromen-3-yl)phenyl acetate (10); 3-(4-methanesulfonylphenyl)-4-methyl-2H-chromen-2-one (11); 8-(acetyloxy)-3-[4-(acetyloxy)phenyl]-4-methyl-2-oxo-2H-chromen-7-yl acetate (12); and 5-(acetyloxy)-3-[4-(acetyloxy) phenyl]-2-oxo-2H-chromen-7-yl acetate (13) in human lung (A549) cancer and normal lung (MRC-9) cell lines at different concentrations for 48 h using crystal violet dye binding assay. The cytotoxic effect of these coumarin derivatives were compared to the standard drug, docetaxel. Furthermore, the effect of the most active compound on the cell-cycle using propidium iodide, mitochondrial membrane potential (MMP) using tetramethyl rhodamine methyl ester (rhodamine-123) and reactive oxygen species (ROS) production using 2',7'-dichlorofluorescin diacetate (PCFDA) were also evaluated. RESULTS: Compound 7: had the greatest cytotoxic effect (cytotoxic concentration, CC50=24 µM) and selectivity (MRC-9; CC50>100 µM; inactive) in the A549 cell line, and caused cells to arrest in the S phase of the cell cycle, loss of MMP and increased ROS production in a concentration-dependent manner. CONCLUSION: These findings suggest that compound 7: could serve as a new lead for the development of novel synthetic compounds with enhanced anticancer activity.

Synthesis and in vitro evaluation of 3-(4-nitrophenyl)coumarin derivatives in tumor cell lines.

Coumarins are naturally-occurring compounds that have attracted considerable interest due to their numerous biological activities depending on their pattern of substitution on the coumarin molecule. In this present investigation, we synthesized 3-(4-nitrophenyl)coumarin derivatives (9a-e) and evaluated their in vitro cytotoxic effect on human lung (A549), breast (MDA-MB-231) and prostate (PC3) cancer cell lines for 48 h using crystal violet dye binding assay. Cytotoxic effects of the most active compound on normal human lung (MRC-9) and breast (MCF-10A) cell lines, cell cycle analysis using flow cytometry and mitochondrial membrane potential (MMP) using Tetramethyl Rhodamine Methyl Ester (TMRM; rhodamine-123) fluorescent dye were also examined. Among the compounds that were evaluated, 9c showed cytotoxic effect (active), caused significant cells arrest (p<0.05) in G0/G1 and S phases of cell cycle and loss of MMP in A459, MDA-MB-231 and PC3 cell lines. Additionally, the cytotoxic effect of 9c was compared to reference drugs (Coumarin and Docetaxel) for comparative study. These results further demonstrate that acetoxy group at C-7 and C-8 positions of 9c are responsible for the observed cytotoxic effect in these cancer cell lines.

Discovery of 3-Arylcoumarin-tetracyclic Tacrine Hybrids as Multifunctional Agents against Parkinson's Disease.

A series of multifunctional directed 3-arylcoumarin-tetracyclic tacrine derivatives was designed and synthesized for the treatment of Parkinson's disease (PD). A number of derivatives (18, 19, 20, 21, and 24) demonstrated significant reduction of aggregation of "human" alpha-synuclein (α-synuclein) protein, expressing on transgenic Caenorhabditis elegans (C. elegans) model NL5901. Moreover, compounds 16, 18, and 24 also exhibited good antioxidant properties and significantly increased the dopamine (DA) content in N2 and NL5901 strains of C. elegans. Interestingly, the protective efficacy of these hybrids seems to be mediated via activation of longevity promoting transcription factor DAF-16. In addition, molecular modeling studies have evidenced the exquisite interaction of most active compounds 18 and 24 with α-synuclein protein. Taken together, the data indicate that the derivatives may be useful leads against aging and age associated PD.

Insight into the interactions between novel coumarin derivatives and human A3 adenosine receptors.

A study focused on the discovery of new chemical entities based on the 3-arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3 AR ligands, with 3-(4'-methylphenyl)-8-(2-oxopropoxy)coumarin (12) being the most potent (Ki =634 nM). None of the compounds showed affinity for the A2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3-arylcoumarin scaffold composes a novel and promising class of A3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.

Antioxidant and antitumor activities of 4-arylcoumarins and 4-aryl-3,4-dihydrocoumarins.

Five 4-arylcoumarins (1c-g) and twelve 3,4-dihydro-4-arylcoumarins (2a-l) were synthesized and tested for antioxidant activity, antitumor activity, toxicity and structure-activity relationships analysis. 4-Arylcoumarins and 3,4-dihydro-4-arylcoumarins that possess two hydroxyl groups in ortho position, such as 1d, 1f, 2a, 2f, 2g and 2h had stronger radical scavenging properties than that of vitamin C (Vit C) in ABTS(+) assay. Kinetic traces of scavenging ABTS(+) and DPPH radicals showed that all the reaction could reached endpoint in 1 min, which was similar with Vit C. 4-Arylcoumarins with 3'-hydroxyl-4'-methylphenyl structural show more efficient NO radical scavenging activity. Three compounds 2e, 1f and 2a, in particular had superior EC50 for NO scavenging than did Vit C. MTT assay indicated that one compound in particular had a potential antitumor effect, inhibiting proliferation of BGC-823 cells and almost completely killing them at a concentration 62.5 mg/L. With same concentration 100 µg/mL, hemolytic analysis in rabbit red blood cells showed that only two compounds had hemolytic activity with a little more than 5% hemolysis. Injection and oral toxicity tests on Galleria mellonella larvae showed that none of the tested 4-arylcoumarins significantly affected their appetite, viability and mortality.