Mechanistic Actions between Garcinia atroviridis Essential Oil and 2 Deoxy-d-glucose in Cultured PANC-1 Human Pancreatic Cancer Cells

Pancreatic cancer is an aggressive disease that progresses in a relatively symptom-free manner; thus, is difficult to detect and treat. Essential oil is reported to exhibit pharmacological properties, besides its common and well-known function as aromatherapy. Therefore, this study herein aimed to investigate the anti-proliferative effect of essential oil extracted from leaves of Garcinia atroviridis (EO-L) against PANC-1 human pancreatic cancer cell line. The cell growth inhibitory concentration at 50% (IC₅₀) and selective index (SI) values of EO-L analyses were determined as 78 µg/mL and 1.23, respectively. Combination index (CI) analysis revealed moderate synergism (CI values of 0.36 to 0.75) between EO-L and 2 deoxy-d-glucose (2-DG) treatments. The treatments of PANC-1 cells with EO-L, 2-DG and EOL+2DG showed evidence of depolarization of mitochondrial membrane potential, cell growth arrest and apoptosis. The molecular mechanism causing the anti-proliferative effect between EO-L and 2-DG is potentially through pronounced up-regulation of P53 (4.40-fold), HIF1α (1.92-fold), HK2 (2.88-fold) and down-regulation of CYP3A5 (0.11-fold), as supported by quantitative mRNA expression analysis. Collectively, the current data suggest that the combination of two anti-proliferative agents, EO-L and 2-DG, can potentially be explored as therapeutic treatments and as potentiating agents to conventional therapy against human pancreatic cancer.     

Synthesis and identifications of potential metabolites as biomarkers of the synthetic cannabinoid AKB-48

AKB-48 belongs to the family of synthetic cannabinoids. It has strong binding affinity to CB₁ receptor and is psychoactive. It is banned in many countries including USA, Japan, Germany, New Zealand, Singapore and China etc. But the difficulty in detecting the parent compound in urine samples highlights the importance of studies of its metabolites. Here we report the synthesis of 19 potential metabolites of AKB-48, among which, compounds 2, 9, 10, 30 and 31, together with the commercially available substance 5 were identified as metabolites of AKB-48 by comparison with one authentic human urine sample and human liver microsomal data. Compounds 10 and 30 could be of use as biomarkers in detecting AKB-48 in human urine samples.     

Studies on mimicry of naturally occurring annonaceous acetogenins: non-THF analogues leading to remarkable selective cytotoxicity against human tumor cells

A class of structurally simplified analogues of the naturally occurring annonaceous acetogenins were developed, amongst which some non-THF analogues showed remarkable cytotoxicities against tumor cell lines, as well as good selectivity between human tumor cells and normal cells. The synthetic routes were significantly shortened because of the removal of the chiral centers bearing the THF rings on the natural templates. This simplification also provides access to the parallel synthesis of these mimics by a combinatorial strategy. The remaining stereogenic centers at the positions alpha to the ethereal links were introduced by the Chiron approach from the easily accessible chiral building blocks 6a and/or 6b, made in turn from L-ascorbic acid or D-mannitol, while the one in the butenolide segment was taken from L-lactate. All four diastereomeric non-THF analogues 2a-2d showed remarkable activity against the HCT-8 cell line, and better differentiation was found when testing against the HT-29 cell line. It was also discovered that both the butenolide and ethylene glycol subunits play essential roles in the cytotoxicities against tumor cell lines, while the 10-substituted hydroxy group and the absolute configuration of methyl group at the butenolide moiety are less important for their activity.     

Synthesis,DNA-binding,and cytotoxic studies on three copper(II) complexes of unsymmetrical synthetic analogues of curcumin

Copper(II) chelates of three unsymmetrical synthetic analogs of curcumin, namely (2E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone(1), (2E)-2-(3,4-dihydroxybenzylidene)-5-((E)-3-(3,4-dihydroxyphenyl)acryloyl)cyclopentanone(2), and (2E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclopeantanone(3) have been synthesized and characterized by physicochemical and spectroscopic methods. The ligands were in their enolic form and metal complexes have 1 : 2 metal:ligand stoichiometry. The DNA-binding properties of the ligands and their metal complexes were studied by absorption titrations, fluorescence quenching experiments, and viscosity measurements with calf-thymus DNA. The interactions of copper(II) complexes were higher than that of free ligands. The observed intrinsic binding constants reveal moderate interaction of copper(II) complexes with calf-thymus DNA. The binding involves intercalative mode through non-covalent interactions and produced conformational changes in the structure of DNA. The compounds were investigated for their possible cytotoxic and antitumor activities. All the compounds were cytotoxic towards Dalton’s lymphoma ascites cells. It was found that copper chelates are remarkably active compared to free curcumin analogs. Concentrations needed for 50% cell death were 10–22 μg mL^?1 for copper complexes and 27–52 μg mL^?1 for curcumin analogs. Copper complex of 2 with two hydroxyl groups in the phenyl ring was most active towards Dalton’s lymphoma ascites cells (increase in life span 77.91%). Copper(II) complex of 3, which possesses methoxy groups in the phenyl ring system, showed the lowest activity towards increase in lifespan of tumor-bearing mice (increase in lifespan 60.14%). Copper chelates of all curcuminoid analogs showed a significant reduction in solid tumor volume in mice.     

Synthesis and structure revision of tyroscherin, and bioactivities of its stereoisomers against IGF-1-dependent tumor cells

Synthesis of the proposed structure of tyroscherin, a growth inhibitor of IGF-1-dependent cancer cells, was succeeded by one-pot Julia coupling. However, spectral data of the synthetic compound were not identical with those of natural tyroscherin. The stereochemistry of tyroscherin is revised to be 2S,3R,8R,10R by syntheses of stereoisomers. Synthetic tyroscherin showed more potent activity than its stereoisomers against IGF-1-dependent cancer cells.     

靶向鞘氨醇激酶1的Jaspine B类似物的合成及抗肿瘤活性研究

Jaspine B,又称为pachastrissamine,是从冲绳海绵Pachastrissa sp和Jaspis sp中分离得到的一种天然存在的脱水植物鞘氨醇衍生物,其异构体2?epi?jaspine B对鞘氨醇激酶和肿瘤细胞系具有强效抑制活性.在此基础上,我们通过对2?epi?jaspine B进行结构修饰制备其...     

Synthesis and biological evaluation of some novel 1-alkyl-3-methylimidazolium carboxylate ionic liquids as potential antifungal agents

In an effort to discover lead compounds that may be of importance as potent antifungal agents, a series of novel 1-alkyl-3-methylimidazolium carboxylate ionic liquids were efficiently synthesized through a solvent-free ultrasound-assisted quaternization reaction of 1-methylimidazole and alkyl bromides RBr (R = hexyl, octyl) followed by an anion exchange process with selected carboxylate anions (cinnamate, salicylate, crotonate, and oxalate). Quantitative yields obtained were in the range of 86–94%. Structure characterization was done using FT-IR, ¹H-NMR, and ¹³C-NMR spectroscopic techniques. All the synthesized compounds showed in vitro antifungal activity against the fungus Candida albicans with the minimum inhibitory concentrations found to be less than or equal to 1%. Preliminary cytotoxicity assays (trypan blue exclusion and MTT) were performed on all ionic liquids and findings revealed higher lymphocyte viability in 1-hexyl-3-methylimidazolium carboxylate ionic liquids than in 1-octyl-3-methylimidazolium counterparts. No extensive toxicity effect was observed with the carboxylate anion variation. Among the tested compounds, 1-hexyl-3-methylimidazolium crotonate and 1-hexyl-3-methylimidazolium oxalate exhibited the lowest cytotoxicity in the trypan blue exclusion and MTT assays, respectively. Together, our results highlight the potential of carboxylate-based ionic liquids in the development of next-generation antifungal drugs.     

Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis,Structural Study,and Biological Activities

Two silver(I) complexes, bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN³:κN⁴-amino) (4-trifluoromethylphenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) and tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN³-amino)(4-trifluoromethylphenyl)methyl]phosphonate} silver(I) tetrafluoroborate, were prepared starting from the diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-amino)(4-trifluoromethylphenyl)methyl]phosphonate (1) ligand and AgBF₄ salt in Ag/ligand ratios of 1/1 and 1/4, respectively. The structure, stoichiometry, and geometry of the silver complexes were fully characterized by elemental analyses, infrared, single-crystal X-ray diffraction studies, multinuclear NMR, and mass spectroscopies. The binuclear complex ([Ag₂(1)₂(BF₄)₂]; 2) crystallizes in the monoclinic asymmetric space group P2₁/c and contains two silver atoms adopting a {AgN₂F} planar trigonal geometry, which are simultaneously bridged by two oxadiazole rings of two ligands, while the mononuclear complex ([Ag(1)₄]BF₄; 3) crystallizes in the non-usual cubic space group Fd-3c in which the silver atom binds to four distinct electronically enriched nitrogen atoms of the oxadiazole ring, in a slightly distorted {AgN₄} tetrahedral geometry. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct with half-maximal inhibitory concentration (IC₅₀) values of 8.3 ± 1.0 and 14.4 ± 0.6 μM, respectively. Additionally, the interactions of the ligand and the mononuclear complex with Vascular Endothelial Growth Factor Receptor-2 and DNA were evaluated by molecular docking methods.     

First Evidence of a Combination of Terpinen-4-ol and α-Terpineol as a Promising Tool against ESKAPE Pathogens

Antimicrobial resistance is a major public health issue raising growing concern in the face of dwindling response options. It is therefore urgent to find new anti-infective molecules enabling us to fight effectively against ever more numerous bacterial infections caused by ever more antibiotic-resistant bacteria. In this quest for new antibacterials, essential oils (or compounds extracted from essential oils) appear to be a promising therapeutic option. In the present work, we investigate the potential antibacterial synergy between a combination of terpinen-4-ol and α-terpineol (10:1) compared to standard tea tree oil. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined. Then, time kill assays, in vitro cytotoxicity and bactericidal activity on latent bacteria (persisters) were investigated. Finally, an in silico study of the pharmacokinetic parameters of α-terpineol was also performed. Altogether, our data demonstrate that the combination of terpinen-4-ol and α-terpineol might be a precious weapon to address ESKAPE pathogens.     

Synthesis,biological evaluation,and molecular docking study of pyridine clubbed 1,3,4-oxadiazoles as potential antituberculars

A series of pyridine clubbed 1,3,4-oxadiazole derivatives were efficiently synthesized, characterized by standard spectral techniques and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H₃₇Ra and Mycobacterium bovis BCG in active and dormant state using an established methods. Compounds 5a, 5m, and 5t were identified as the most active compounds against MTB. Molecular docking was performed against MTB enoyl-ACP (CoA) reductase (FabI/ENR/InhA) enzyme to predict the binding modes and affinity. The theoretical predictions from molecular docking could establish a link between the observed biological activity and the binding affinity shedding light into specific bonded and non-bonded interactions influencing the activity. The active compounds were studied for cytotoxicity against three cell lines and were found to be non-cytotoxic. Specificity of these compounds was checked by screening them for their antibacterial activity against four bacterial strains.     

Synthesis of substituted amido-isogranulatimide analogues as potential checkpoint1 kinase inhibitors

Two new regioisomeric series of substituted amido-isogranulatimide analogues were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. The experimental conditions of the last photocyclization step were determinant to obtain one or the other series.     

Design and automated generation of artificial estrogen receptor as potential endocrine disruptor chemical binders

We here report on our results concerning the systematic design and synthesis of a new type of artificial estrogen receptor candidates. Our interest herein originates from the known estrogenic activity of endocrine disrupting chemicals, environmental pollutants that have attracted increased attention due to their interference with the endocrine and reproductive system of wildlife and humans. An automated protocol for the generation of libraries of potential artificial receptors is described. The resulting structures could find application in novel SPE cartridges for EDC-preconcentration.     

Synthesis and biological evaluation of 3-amino-2-pyrones as selective cyclooxygenase-1 (COX-1) inhibitors

A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for inhibiting cyclooxygenase（COX） activity.This study has led to the identification of COX-1-selective inhibitors.Among the tested compounds,the compound 5j exhibited the most potent COX-1 inhibitory activity(IC₅₀ = 19.32μg/mL) and COX-1 selectivity index（SI = 41.98）.     

Quantitative analysis of isoprene units in natural rubber and synthetic polyisoprene using 1H-NMR spectroscopy with an internal standard

Isoprene units in natural rubber (NR) and its synthetic analogues were quantified by ¹H-NMR spectroscopy using polyethylene glycol (PEG) as an internal standard. The effect of PEG and rubber concentrations, molar ratio of rubber/PEG, measuring temperature and scan number on the quantification was investigated to establish the respective working range. Analysis of commercial grades of NR revealed that the differences in 1,4 isoprene content is caused by the production process and feedstock, in which proteins and lipids were found to be the major impurity in NR. Gel fraction of NR has insignificant effect on the measurement of 1,4 isoprene content. Furthermore, the new method was found to produce good results for the quantification of 1,4 and 3,4 units of synthetic polyisoprenes.     

Spirocyclization strategy toward indole phytoalexins. The first synthesis of (±)-1-methoxyspirobrassinin, (±)-1-methoxyspirobrassinol, and (±)-1-methoxyspirobrassinol methyl ether

The first syntheses of cruciferous indole phytoalexins (±)-1-methoxyspirobrassinin, (±)-1-methoxyspirobrassinol, (±)-1-methoxyspirobrassinol methyl ether as well as a new syntheses of phytoalexins (±)-spirobrassinin and cyclobrassinin were achieved by dioxane dibromide (DDB)-mediated spirocyclization of brassinin and its 1-substituted derivatives.     

Prenylated flavonoids and dihydrophenanthrenes from the leaves of Epimedium brevicornu and their cytotoxicity against HepG2 cells

Phytochemical study on the leaves of Epimedium brevicornu finally led to the isolation of four prenylated flavonoids (1–4) and three dihydrophenanthrenes (5–7), of which 1, 2, 5 and 7 were new compounds. The structures of these compounds were established mainly by spectroscopic techniques, including NMR spectroscopy and mass spectrometry. These isolates exhibited the cytotoxic activities against HepG2 cells with the IC₅₀ values of 32.8–87.3 μM.     

Green synthetic approaches: solventless synthesis of polyfunctionally substituted aromatics as potential versatile building blocks in organic synthesis utilizing enaminones and enaminonitriles as precursors

Abstract

A variety of 1,3,5-trisubstituted benzenes could be obtained upon heating enaminones in absence of solvent over montmorillonite-K-10. Heating mixtures of two different enaminones 2a–d have also afforded 1,3,5-trisubstituted benzenes 7b–d and 8b–d resulting from self-condensation of one enaminone with two molecules of the other enaminone. Heating enaminone 2b with ethyl propiolate afforded a mixture of triaroylbenzene 3b in addition to diaroylbenzoic acid esters 11 and 1,3,5-aroylbenzene dicarboxylate 12. On the other hand, reaction of enaminone derivative 2b with dimethyl acetylenedicarboxylate has afforded 2-oxopyran-4-carboxylic acid derivative 15. 2-Aminoprop-1-ene-1,1,3-tricarbonitrile 16 was reacted with enaminones to yield polysubstituted benzenes 19a–c. Likewise the reaction of 2-aminoprop-1-ene-1,1,3-tricarbonitrile 16 with benzylidenemalononitrile has afforded polysubstituted benzenes 24.     

Identification of potential inhibitors against nuclear Dam1 complex subunit Ask1 of Candida albicans using virtual screening and MD simulations

Identification of hit compounds against specific target form the starting point for a drug discovery program. A consistent decline of new chemical entities (NCEs) in recent years prompted a challenge to explore newer approaches to discover potential hit compounds that in turn can be converted into leads, and ultimately drug with desired therapeutic efficacy. The vast amount of omics and activity data available in public databases offers an opportunity to identify novel targets and their potential inhibitors. State of the art in silico methods viz., clustering of compounds, virtual screening, molecular docking, MD simulations and MMPBSA calculations were employed in a pipeline to identify potential ‘hits’ against those targets as well whose structures, as of now, could only predict through threading approaches. In the present work, we have started from scratch, amino acid sequence of target and compounds retrieved from PubChem compound database, modeled it in such a way that led to the identification of possible inhibitors of Dam1 complex subunit Ask1 of Candida albicans. We also propose a ligand based binding site determination approach. We have identified potential inhibitors of Ask1 subunit of a Dam1 complex of C. albicans, which is required to prevent precocious spindle elongation in pre-mitotic phases. The proposed scheme may aid to find virtually potential inhibitors of other unique targets against candida.     

The design and synthesis of novel 3-[2-indol-1-yl-ethyl]-1H-indole derivatives as selective inhibitors of CDK4

We present the design, synthesis and biological activity of novel 3-[2-indol-1-yl-ethyl]-1H-indole selective inhibitors of CDK4.