ABSTRACT
A new series of substituted benzo[h]chromene, benzochromenopyrimidine, and benzochromenotriazolopyrimidine derivatives were synthesized via chemical transformations of iminonitrile, ethoxymethylene amino, and cyanomethylene functionalities. The chemical structures of the synthesized compounds were assured by spectroscopic data and elemental analysis. The larvicidal efficacy of these compounds against Culex pipiens L. larvae was investigated, revealing potent insecticidal activity, particularly for compounds 6, 10, and 16, exceeding that of the standard insecticide chlorpyrifos. The mode of action of these compounds was explored through molecular docking studies, indicating their potential as acetylcholine esterase (AChE) inhibitors and nicotinic acetylcholine receptors (nAChR) blockers. The structure-activity relationship analysis highlighted the influence of substituents and fused heterocyclic rings on larvicidal potency. These findings suggest that the synthesized compounds hold promise as potential candidates for developing novel and effective mosquito control agents.
Subject(s)
Benzopyrans , Culex , Insecticides , Larva , Molecular Docking Simulation , Animals , Culex/drug effects , Larva/drug effects , Insecticides/pharmacology , Insecticides/chemistry , Insecticides/chemical synthesis , Structure-Activity Relationship , Benzopyrans/pharmacology , Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Models, Molecular , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Receptors, Nicotinic/metabolism , Molecular StructureABSTRACT
Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD.
Subject(s)
Alzheimer Disease , Drug Discovery , Animals , Humans , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Benzopyrans/chemistry , Benzopyrans/pharmacology , Benzopyrans/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Molecular Structure , Structure-Activity Relationship , Acridines/chemical synthesis , Acridines/chemistry , Acridines/pharmacologyABSTRACT
We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.
Subject(s)
Antineoplastic Agents , Drug Screening Assays, Antitumor , Enhancer of Zeste Homolog 2 Protein , Hypoxia-Inducible Factor 1, alpha Subunit , Lung Neoplasms , Pyridones , Humans , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Enhancer of Zeste Homolog 2 Protein/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Pyridones/chemistry , Pyridones/pharmacology , Pyridones/chemical synthesis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Molecular Structure , Dose-Response Relationship, Drug , Cell Proliferation/drug effects , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacology , Benzopyrans/chemical synthesis , Cell Movement/drug effectsABSTRACT
The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3',2'-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6-8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds.
Subject(s)
Anti-Infective Agents , Antineoplastic Agents , Benzopyrans , Microbial Sensitivity Tests , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzopyrans/pharmacology , Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Cell Line, Tumor , Molecular Structure , Structure-Activity Relationship , Bacteria/drug effectsABSTRACT
Using (S)-decursinol isolated from root of Angelica gigas Nakai (AGN), we semi-synthesized and evaluated a series of both enantiomerically pure decursin derivatives for their antiproliferative activities against A549 human lung cancer cells. All synthesized compounds showed a broad spectrum of inhibitory activities against the growth of A549 cells. Especially, compound (S)-2d with (E)-(furan-3-yl)acryloyl group showed the most potent activity (IC50: 14.03 µM) against A549 cancer cells as compared with the reference compound, decursin (IC50: 43.55 µM) and its enantiomer, (R)-2d (IC50: 151.59 µM). Western blotting assays indicated that (S)-2d more strongly inhibited Janus kinase 1 (JAK1) and signal transducer and activator of transcription activation 3 (STAT3) phosphorylation than decursin in a dose-dependent manner, while having no effect on CXCR7 overexpression and total STAT3 level. In addition, (S)-2d induced cell cycle arrest at G1 phase and subsequent apoptotic cell death in A549 cancer cells. Our combined analysis of molecular docking studies and biological data suggests that the inhibition of JAK1 with (S)-2d resulted in loss of STAT3 phosphorylation and inhibition of cell growth in A549 cancer cells. These overall results strongly suggest that (S)-2d (MRC-D-004) as a novel JAK1 inhibitor may have therapeutic potential in the treatment of A549 human lung cancers by targeting the JAK1/STAT3 signaling pathway.
Subject(s)
Apoptosis , Benzopyrans , Butyrates , Cell Proliferation , Drug Screening Assays, Antitumor , Molecular Docking Simulation , STAT3 Transcription Factor , Humans , Cell Proliferation/drug effects , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Benzopyrans/pharmacology , Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Butyrates/pharmacology , Butyrates/chemistry , Butyrates/chemical synthesis , Apoptosis/drug effects , A549 Cells , Stereoisomerism , Dose-Response Relationship, Drug , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Molecular Structure , Angelica/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistryABSTRACT
Stereoselective synthesis is essential for propelling mainstream academia toward a relentless pursuit of novel and cutting-edge strategies for constructing molecules with unparalleled precision. Naturally derived benzopyrans, benzopyrones, and flavonoids are an essentially prominent group of oxa-heterocycles, highly significant targets in medicinal chemistry owing to their extensive abundance in biologically active natural products and pharmaceuticals. The molecular complexity and stereoselectivity induced by heterocycles embedded with C-glycosides have attracted considerable interest and emerged as a fascinating area of research for synthetic organic chemists. This present article emphasizes the existing growths in the strategies involving the diastereoselective synthesis of C-glycosylated benzopyrans, benzopyrones, and flavonoids using naturally acquired glycones as chiral synthons.
Subject(s)
Benzopyrans , Biological Products , Flavonoids , Glycosides , Flavonoids/chemistry , Flavonoids/chemical synthesis , Stereoisomerism , Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Glycosides/chemistry , Glycosides/chemical synthesis , Pyrones/chemistry , Pyrones/chemical synthesis , Glycosylation , Molecular StructureABSTRACT
Fatty liver disease affects at least 25 percent of the population worldwide and is a severe metabolic syndrome. Viscosity is closely related to fatty liver disease, so it is urgent to develop an effective tool for monitoring viscosity. Herein, a NIR fluorescent probe called MBC-V is developed for imaging viscosity, consisting of dimethylaniline and malonitrile-benzopyran. MBC-V is non-fluorescent in low viscosity solutions due to intramolecular rotation. In high viscosity solution, the intramolecular rotation of MBC-V is suppressed and the fluorescence is triggered. MBC-V has long emission wavelength at 720 nm and large Stokes shift about 160 nm. Moreover, MBC-V can detect changes in cell viscosity in fatty liver cells, and can image the therapeutic effects of drug in fatty liver cells. By taking advantage of NIR emission, MBC-V can be used as an imaging tool for fatty liver disease and a way to evaluate the therapeutic effect of drug for fatty liver disease.
Subject(s)
Aniline Compounds , Fatty Liver , Fluorescent Dyes , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Animals , Viscosity , Mice , Fatty Liver/diagnostic imaging , Fatty Liver/drug therapy , Aniline Compounds/chemistry , Optical Imaging , Humans , Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Nitriles/chemistryABSTRACT
A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100⯵g/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11⯵g/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC50 values of 0.975 ± 0.04 and 0.584 ± 0.02⯵g/mL, respectively, compared to Acarbose (IC50 = 0.805 ± 0.03⯵g/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC50 values of 3.453 ± 0.14 and 4.653 ± 0.04⯵g/mL compared to Pioglitazone (IC50 = 4.884±0.29⯵g/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.
Subject(s)
Benzopyrans , Diabetes Mellitus, Type 2 , Drug Design , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents , PPAR gamma , alpha-Amylases , alpha-Glucosidases , PPAR gamma/metabolism , PPAR gamma/antagonists & inhibitors , Benzopyrans/chemistry , Benzopyrans/pharmacology , Benzopyrans/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemical synthesis , alpha-Glucosidases/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , alpha-Amylases/antagonists & inhibitors , alpha-Amylases/metabolism , Humans , Structure-Activity Relationship , Molecular Structure , Molecular Docking Simulation , Drug Evaluation, Preclinical , Drug Discovery , Dose-Response Relationship, DrugABSTRACT
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Subject(s)
Metabolic Syndrome , Quinolines , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/chemical synthesis , Structure-Activity Relationship , Humans , Peroxisome Proliferator-Activated Receptors/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Molecular Structure , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Macrophages/drug effects , Macrophages/metabolism , Dose-Response Relationship, Drug , Benzopyrans/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Animals , MiceABSTRACT
2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzopyrans/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Vitamin E/analogs & derivatives , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity Relationship , Vitamin E/chemical synthesis , Vitamin E/chemistry , Vitamin E/pharmacologyABSTRACT
An array of 4-aryl-2-amino-4H chromene derivatives were designed, synthesized, and evaluated for cytotoxic activity against four cancer cell lines and two non-cancerous cell lines. The most active candidates were further screened for their in vitro anticancer activity on NCI panel of 60 human cancer cell lines where compounds 2a, 2b, 4a-2, and 2e showed promising activity against various leukemia, non-small lung, renal, prostate, and breast cancer cell lines, particularly against NCI-H522 non-small lung cancer cell line (GI50 of 0.35-0.60 µM), MCF7 breast cancer cell line (GI50 of 0.34-0.59 µM), and MDA-MB-468 breast cancer cell line (GI50 of 0.23-0.40 µM). Compound 2b was the most potent against all leukemia and prostate cancer cell lines with GI50 values (0.29-0.60 µM). Compound 2b inhibited the proliferation of MCF-7 and HepG2 cells by inducing cell cycle arrest and apopotosis. 2b downregulated the mRNA abundance of BAX, Apaf-1 and caspase-3 and upregulated BCL-2. The activities of caspase-3 and caspase-9 were declined in MCF-7 and HepG2 cells treated with compound 2b. Compounds 2b and 4a-2 inhibited tubulin polymerization, with an IC50 values of 0.92 and 1.13 µM, respectively. These findings indicate that these synthesized compounds may represent potential drug candidates to inhibit the proliferation of different types of cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzopyrans/pharmacology , Drug Development , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) is applied successfully to highly enantioselective Prins cyclization reactions of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts were designed to withstand the strongly acidic reaction conditions and were found to induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone. We propose that the combination of strong mineral acids and chiral hydrogen-bond-donor catalysts may represent a general strategy for inducing enantioselectivity in reactions that require highly acidic conditions.
Subject(s)
Alcohols/chemical synthesis , Aldehydes/chemistry , Alkenes/chemistry , Hydrochloric Acid/chemistry , Benzopyrans/chemical synthesis , Catalysis , Cyclization , Hydrogen Bonding , Quinine/analogs & derivatives , Quinine/chemistry , Stereoisomerism , Thiourea/analogs & derivatives , Urea/analogs & derivativesABSTRACT
To explore complex biological and chemical systems, pharmaceutical research has effectively included several molecular modeling tools into a range of drug development initiatives. Molecular docking methods are widely employed in current drug design to investigate ligand conformations within macromolecular targets' binding sites. This method also estimates the ligand-receptor binding free energy by assessing critical phenomena involved in the intermolecular recognition process. In an attempt, several natural products have been synthesized in our laboratory. All the synthesized compounds containing (6H-Dibenzo[b,d]pyran-6-one) framework were subjected to molecular docking studies for the inhibition of CYP1B1 and BCL2 proteins using Auto Dock Vina software and the interacting amino acid residues were visualized using Discovery Studio, to look into the binding modalities that might influence their anticancer properties. The in silico molecular docking study outcomes showed that all the synthesized compounds having optimum binding energy and have a decent affinity to the active pocket, thus, they may be considered as a respectable inhibitor of CYP1B1 and BCL2 proteins.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Binding Sites , Computer Simulation , Cytochrome P-450 CYP1B1/antagonists & inhibitors , Drug Design , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Conformation , Molecular Docking Simulation , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Receptors, Drug/drug effectsABSTRACT
Smart responsive materials have attractive application prospects due to their tunable behaviors. In this work, we design novel spiropyran (SP)-based magnetic nanoparticles (MNP-SP) with dual response to ultraviolet light and pH and apply them to the enrichment of phosphopeptides. SP is modified on the surface of magnetic nanoparticles through a simple esterification reaction, based on which an MNP-SP-MS phosphopeptide identification platform is established. The capture and release of phosphopeptides are facilely adjusted by changing external light and the pH of the solution. The smart responsive MNP-SP has fast magnetic response performance, high sensitivity (detection limit of 0.4 fmol), and good reusability (6 cycles). In addition, MNP-SP is used for the enrichment of phosphopeptides in skimmed milk, human saliva, and human serum samples, indicating that it is an ideal adsorbent for enriching low-abundance phosphopeptides in complex biological environments.
Subject(s)
Benzopyrans/chemistry , Indoles/chemistry , Nitro Compounds/chemistry , Phosphopeptides/chemistry , Adsorption , Animals , Benzopyrans/chemical synthesis , Cattle , Humans , Hydrogen-Ion Concentration , Indoles/chemical synthesis , Magnetite Nanoparticles/chemistry , Milk/chemistry , Molecular Structure , Nitro Compounds/chemical synthesis , Particle Size , Surface PropertiesABSTRACT
Herein, a series of aryl-substituted derivatives of 3-amino-1-aryl-9-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-4q) were designed and synthesized via reaction of 7-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. Among the tested benzochromene, the known compound 4e and four novel compounds 4f, 4j, 4k, 4m exhibited the highest cytotoxicity towards a panel of six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, RPMI 7951, and PC-3. Compound 4j with 2,4-dichloro substitution on the pendant phenyl ring exhibited the highest broad-spectrum cytotoxicity towards all tested cancer cell lines. Compounds 4e, 4f, 4j, 4k, 4m were further selected to study the mechanism of cellular toxicity using the triple-negative breast cancer cells MDA-MB-231. Compounds 4e, 4f, 4j, 4k, 4m induced accumulation of the treated MDA-MB-231 cells in the S phase and 4k additionally in the G2/M phase of the cell cycle. Compounds 4e, 4f, 4j, 4k, 4m induced dissipation of mitochondrial transmembrane potential and activation of caspase 3/7 in MDA-MB-231 cells with 4j being one of the most active. In an in vivo model, compound 4j and less efficiently 4e and 4f inhibited growth and proliferation and triggered DNA fragmentation in MDA-MB-231 xenografts grown on chick chorioallantoic membranes. SAR study confirmed that the 2,4-dichloro substitution pattern on the pendant phenyl ring enhanced the cytotoxic activity of benzochromene.
Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Substituted amide derivatives of C4-ageratochromene dimer analog (19) were synthesized through structural modification of precocene-I (4a), isolated from the essential oil of Ageratum conyzoides L. The target compounds (18-20, 23I-VI, 24I-VI, and 25I-VI) were evaluated for their bone-forming effect using osteoblast differentiation assay. Seven compounds (23I, 23II, 23IV, 23VI, 24III, 24VI, and 25VI) presented good activity within 1 pM-1 nM concentration. At 1 pM concentration, the most active compound i.e. 23II showed effective mineralization of osteoblast cells along with expression of osteogenic marker genes viz RUNX 2, BMP-2, and type 1 collagen (Type-1 col) without any toxicity towards osteoblast cells. Single crystal X-ray analysis of 18 and 20 revealed that the core nucleus of these molecules bear phenyl rings in a Trans-stilbenoid system and had a good structural correlation with 17ß-estradiol (1) and diethylstilbestrol (DES, 3). In-silico study about 23II showed its structural complementarities with the LBD of estrogen receptor (ER) which indicated possible ER-mediated activity of compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Bone Density Conservation Agents/chemical synthesis , Bone Density Conservation Agents/pharmacology , Ageratum/chemistry , Animals , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Drug Discovery , Female , Humans , Mice , Models, Molecular , Molecular Structure , Osteoblasts , Receptors, Estrogen/metabolism , Structure-Activity RelationshipABSTRACT
Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.
Subject(s)
Benzopyrans/chemical synthesis , Monosaccharides/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Amino Acid Sequence , Benzopyrans/metabolism , Carbamates/chemistry , Humans , Kinetics , Models, Molecular , Monosaccharides/metabolism , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/metabolism , Rhamnose/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Structure-Activity RelationshipABSTRACT
A series of pyrimidine-containing 4H-chromen-4-one derivatives were designed and synthesized by combining bioactive substructures. Preliminary biological activity results showed that most of the compounds displayed significant inhibitory activities inâ vitro against Xanthomonas axonopodis pv. Citri (X. axonopodis), Xanthomonas oryzae pv. oryzae (X. oryzae) and Ralstonia solanacearum (R. solanacearum). In particular, compoundâ 2-[(3-{[5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4c) demonstrated a good inhibitory effect against X. axonopodis and X. oryzae, with the half-maximal effective concentration (EC50 ) values of 15.5 and 14.9 µg/mL, respectively, and compoundâ 2-[(3-{[5,7-Dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4h) showed the best antibacterial activity against R. solanacearum with an EC50 value of 14.7 µg/mL. These results were better than commercial reagents bismerthiazol (BT, 51.7, 70.1 and 52.7 µg/mL, respectively) and thiodiazole copper (TC, 77.9, 95.8 and 72.1 µg/mL, respectively). In vivo antibacterial activity results indicated that compoundâ 4c displayed better curative (42.4 %) and protective (49.2 %) activities for rice bacterial leaf blight than BT (35.2, 39.1 %) and TC (30.8, 27.3 %). The mechanism of compoundâ 4c against X. oryzae was analyzed through scanning electron microscopy (SEM). These results indicated that pyrimidine-containing 4H-chromen-4-one derivatives have important value in the research of new agrochemicals.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzopyrans/chemistry , Drug Design , Pyrimidines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Crystallography, X-Ray , Microbial Sensitivity Tests , Molecular Conformation , Oryza/growth & development , Oryza/microbiology , Plant Diseases/microbiology , Plant Diseases/therapy , Ralstonia solanacearum/drug effects , Structure-Activity Relationship , Sulfhydryl Compounds/pharmacology , Thiadiazoles/pharmacology , Xanthomonas/drug effectsABSTRACT
Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 µM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.
Subject(s)
Benzopyrans , Drug Design , Enzyme Inhibitors , Exonucleases/antagonists & inhibitors , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Benzopyrans/pharmacology , Cell Line , Drug Evaluation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Exonucleases/metabolism , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the Gq-coupled P2Y6 receptor (P2Y6R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6R-expressing astrocytoma cells elicited by native P2Y6R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6R, which is a target for inflammatory, neurodegenerative and metabolic diseases.