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Rdc2 is a flavin-dependent halogenase from Pochonia chlamydosporia . Through the introduction of a His 6 -tag to both the N- and C-termini, the isolation yield of Rdc2 from Escherichia coli using Ni-NTA affinity chromatography was increased by three-fold. In vitro reaction of Rdc2 and a flavin reductase (Fre) with seven different hydroxyquinolines revealed that 3-hydroxyquinoline ( 3 ), 5-hydroxyquinoline ( 5 ), 6-hydroxyquinoline ( 6 ), and 7-hydroxyquinoline ( 7 ) can be specifically halogenated. These products were prepared by incubating the corresponding substrates with IPTG-induced E. coli BL21(DE3)/Rdc2. They were respectively characterized as 3-hydroxy-4-chloroquinoline ( 3a ), 5-hydroxy-6-chloroquinoline ( 5a ), 5-chloro-6-hydroxyquinoline ( 6a ), and 7-hydroxy-8-chloroquinoline ( 7a ) by NMR and MS analyses. This work represents the first enzymatic preparation of chlorohydroxyquinolines and provides a ‘green’ method to synthesize this group of medicinally important compounds.

Antibiotics are widely used to improve the health and yields of farmed animals, including fish, but their use is accompanied by undesirable ecological effects. Relatively little is known about the water-body burden of antibiotics and their influence on primary productivity in aquaculture ecosystem. In this study, antibiotics usage within 24 fishponds, covering 4 areas, sampled 5 times, and having 5 fish species, was investigated surrounding Tai Lake in China. The study analyzed 15 antibiotics (including 5 sulfonamides, 2 quinolones, 3 β-lactams, 3 tetracyclines, 1 amphenicol, and 1 macrolide), and all of them were detected in water samples, with a detection frequency of 2-60%. Sulfonamides were the most prevalent, and concentrations of sulfamethoxazole, sulfamonomethoxine, and florfenicol being over 2000 ng L(-1) in some samples, while the other antibiotics levels ranged from ND (no detection) to 551.18 ng L(-1). Significant differences were observed in antibiotic burden among different regions for total antibiotics, sulfonamides, quinolones, and amphenicols; among time points for quinolones, β-lactams, and tetracyclines; and among species for quinolones and macrolides. Furthermore, basing on the risk quotient (RQ) method, the assessment revealed that florfenicol was of highest risk to algae with RQ values exceeding 0.1, while macrolide erythromycin posed the second highest risk. The partial correlation coefficient between total antibiotics and chlorophyll (a) was -0.035 that clearly indicated total antibiotics were detrimental to green algae growth, while the nutrient input and other physical - chemical factors were much more beneficial. Overall, holistic far-reaching measures of antibiotics control are recommended to preserve aquaculture ecosystem health.

A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer's disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1-42 aggregation, rapid H2O2 scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2 within 200-220min and possesses GPx-like activity (v0=106.0μM·min(-1)), enabling modulation of metal-induced Aβ aggregation.

8-Hydroxyquinolines are heterocyclic compounds characterized by a moderate metal-binding affinity. The interest in 8-hydroxyquinolines has grown exponentially in the last two decades as they are privileged structures for the design of new drug candidates that exert a host of biological effects on various targets. The study of biological activities such as neuroprotection, anticancer, antibacterial, antifungal activity has been further promoted by the synthetic versatility of 8-hydroxyquinoline, which allows the generation of a large number of derivatives. These include numerous multifunctional analogues having the metal-binding motif of 8-hydroxyquinoline. In this review, we have summarized 8-hydroxyquinolines, 8-hydroxyquinoline-like compounds, 8-hydroxyquinoline-loaded nanoparticle systems with respect to their biological activities, interaction with metal ions and mechanisms of action.

Adsorption of lead (II) ions onto cassava starch 5-choloromethyl-8-hydroxyquinoline polymer (CSCMQ) was investigated with the variation in the parameters of pH, contact time, lead (II) ions concentration, temperature and the adsorbent dose. The Langmuir and Freundlich models have been applied. CSCMQ was characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. Results showed that the adsorption process was better described by the Langmuir model. Adsorption kinetics data obtained for the metal ions sorption were investigated using pseudo-first-order, pseudo-second-order and intraparticle diffusion model. The maximum adsorption capacities (qm) were 46.512, 43.859 and 42.735 mg/g at 25, 35 and 45 °C, respectively. The dynamical data fit well with the second-order kinetics model. The results indicate that CSCMQ could be employed as low-cost material for the adsorption of Pb(II) ions from aqueous medium.

// Jessica L. Weatherbee 1 , Jean-Louis Kraus 2 , Alonzo H. Ross 1 1 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA 2 Developmental Biology Institute of Marseille-Luminy (IBDML), Aix-Marseille University (AMU) and CNRS, UMR 7288, IBDML, Case 907, Marseille, France Correspondence to: Alonzo H. Ross, email: Alonzo.Ross@umassmed.edu Keywords: glioblastoma, endoplasmic reticulum stress, ATF4, apoptosis, DNA double strand breaks Received: April 07, 2016 Accepted: May 19, 2016 Published: June 07, 2016 ABSTRACT Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor. Radiation in combination with temozolomide (TMZ), the current chemotherapeutic for GBMs, only provides 12–14 months survival post diagnosis. Because GBMs are dependent on both activation of the DNA damage pathway and the endoplasmic reticulum (ER) stress response, we asked if a novel ER stress inducing agent, JLK1486, increases the efficacy of TMZ. We found that the combination of TMZ+JLK1486 resulted in decreased proliferation in a panel of adherent GBM cells lines and reduced secondary sphere formation in non-adherent and primary lines. Decreased proliferation correlated with increased cell death due to apoptosis. We found prolonged ER stress in TMZ+JLK1486 treated cells that resulted in sustained activation of the unfolded protein response (UPR) through increased levels of BiP, ATF4, and CHOP. In addition, TMZ+JLK1486 treatment caused decreased RAD51 levels, impairing DNA damage repair. Furthermore, we found delayed time to tumor doubling in TMZ+JLK1486 treated mice. Our data shows that the addition of JLK1486 to TMZ increases the efficaciousness of the treatment by decreasing proliferation and inducing cell death. We propose increased cell death is due to two factors. One, prolonged ER stress driving the expression of the pro-apoptotic transcription factor CHOP, and, second, unresolved DNA double strand breaks, due to decreased RAD51 levels. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between unresolved ER stress and the DNA damage response pathway.

Actinomycete bacteria of the common genus Streptomyces can be routinely isolated from shallow and deep ocean sediments. Although commonly considered a terrestrial genus, and most abundantly found in soil, Streptomyces strains are found that have distinct requirements for seawater and routinely do not show significant similarity, with terrestrial strains by 16S ribosomal DNA phylogenetic sequence comparisons. Our examination of the culture broth of a Streptomyces sp., strain CNP975, isolated from a local La Jolla, California sediment sample, resulted in the isolation of actinoquinolines A and B (1, 2), which show significant inhibition of the arachidonic acid pathway enzymes cyclooxygenases-1 and -2. The new compounds contain the 3-hydroxyquinaldic acid (3HQA) motif found in numerous peptide antibiotics. In the actinoquinolines, 3HQA forms an amide linkage with a linear six-carbon fragment, formally a 2, 6-diamino-1, 5-dihydroxyhexane unit, a component of likely amino acid reductive off-loading origin. Actinoquinoline A illustrated amide rotational isomerism leading to complex NMR spectral data. Actinoquinoline B was assigned as the C-13 aldehyde analog isolated as an intramolecular hemiacetal. Reduction of 2 with NaBH4 yielded actinoquinoline A thus confirming the relative configurations of all centers in the actinoquinolines.

Inhibitory modulation toward de novo protein aggregation is likely to be a vital and promising therapeutic strategy for understanding the molecular etiology of amyloid related diseases such as Alzheimer's disease (AD). The building up of toxic oligomeric and fibrillar amyloid aggregates in the brain plays host to a downstream of events, causing damage to axons, dendrites, synapses, signaling, transmission, and finally cell death. Herein, we introduce a novel conjugated polymer (CP), hydroxyquinoline appended polyfluorene (PF-HQ), which has a typical "amyloid like" surface motif and exhibits inhibitory modulation effect on amyloid β (Aβ) aggregation. We delineate inhibitory effects of PF-HQ based on Thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism (CD), and Fourier transform infrared (FTIR) studies. The amyloid-like PF-HQ forms nano coaggregates by templating with toxic amyloid intermediates and displays improved inhibitory impacts toward Aβ fibrillation and diminishes amyloid cytotoxicity. We have developed a CP based modulation strategy for the first time, which demonstrates beneficiary amyloid-like surface motif to interact efficiently with the protein, the pendant side groups to trap the toxic amyloid intermediates as well as optical signal to acquire the mechanistic insight.

Accumulation of evidence has demonstrated high levels of iron in the central nervous system of both sporadic and familial amyotrophic lateral sclerosis (ALS) patients and in ALS mouse models. In accordance, iron chelation therapy was found to exert beneficial effects on ALS mice. Our group has designed and synthesized series of multifunctional non-toxic, brain permeable iron-chelating compounds for neurodegenerative diseases. Recent study has shown that co-administration of one of these drugs, VAR10303 with high calorie/energy-supplemented diet (VAR-ced), initiated after the appearance of disease symptoms improved motor performance, extended survival, and attenuated iron accumulation and motoneuron loss in SOD1(G93A) mice. Since VAR was found to exert diverse pharmacological properties associated with mitochondrial biogenesis in the gastrocnemius (GNS) muscle, we further assessed in the current study the impact of VAR-ced on additional neurorescue-associated molecular targets in the GNS and frontal cortex in SOD1(G93A) mice. The results show that VAR-ced treatment upregulated the expression of various HIF-1α-target glycolytic genes and elevated the levels of Bcl-2, neurotrophic factors, and AKT/GSK3β signaling in the GNS and frontal cortex of SOD1(G93A) mice, suggesting that these protective regulatory parameters regulated by VAR-ced treatment may be associated with the beneficial effects of the drug observed on ALS mice.

Tumour growth is closely related to the development of new blood vessels to supply oxygen and nutrients to cancer cells. Without the neovascular formation, tumour volumes cannot increase and undergo metastasis. Antiangiogenesis is one of the most promising approaches for antitumour therapy. The exploration of new antiangiogenic agents would be helpful in antitumour therapy. Quinoline is an aromatic nitrogen compound characterized by a double-ring structure which exhibits a benzene ring fused to pyridine at two adjacent carbon atoms. The high stability of quinoline makes it preferable in a variety of therapeutic and pharmaceutical applications, including antitumour treatment. This work is to examine the potential antiangiogenic activity of the synthetic compound 2-Formyl-8-hydroxy-quinolinium chloride. We found that 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of human umbilical vein endothelial cells in vitro. Using the diethylnitrosamine-induced hepatocarcinogenesis model, 2-Formyl-8-hydroxy-quinolinium chloride showed strong antiangiogenic activity. Furthermore, 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of large Hep3B xenografted tumour from the nude mice. We assume that 2-Formyl-8-hydroxy-quinolinium chloride could be a potential antiangiogenic and antitumour agent and it is worthwhile to further study its underlying working mechanism.

A new method was developed for the photoinduced dearomatization of arenes through an intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer (ESIPT) in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles. It provides rapid access to novel heterocycles, cyclohexadieno-oxazolidino-quinolinols, as valuable synthons for a broad range of post-photochemical transformations.

Quinoline, which belongs to N-heterocyclic compounds, occurs naturally in the environment and is used in numerous industrial processes. The structures of various chemicals, such as dyes and medicines, are based on this compound. Due to that fact, quinoline and its derivatives are widely distributed in environment and can exert toxic effects on organisms from different trophic levels. The ability of the filamentous fungus Cunninghamella elegans IM 1785/21Gp to degrade quinoline and modulate the membrane composition in response to the pollutant was studied. C. elegans IM 1785/21Gp removes quinoline with high efficiency and transforms the pollutant into two novel hydroxylated derivatives, 2-hydroxyquinoline and 3-hydroxyquinoline. Moreover, due to the disruption in the membrane stability by quinoline, C. elegans IM 1785/21Gp modulates the fatty acid composition and phospholipid profile.

Bacterial programmed cell death and quorum sensing are direct examples of prokaryote group behaviors, wherein cells coordinate their actions to function cooperatively like one organism for the benefit of the whole culture. We demonstrate here that 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO), a Pseudomonas aeruginosa quorum-sensing-regulated low-molecular-weight excreted molecule, triggers autolysis by self-perturbing the electron transfer reactions of the cytochrome bc1 complex. HQNO induces specific self-poisoning by disrupting the flow of electrons through the respiratory chain at the cytochrome bc1 complex, causing a leak of reducing equivalents to O2 whereby electrons that would normally be passed to cytochrome c are donated directly to O2. The subsequent mass production of reactive oxygen species (ROS) reduces membrane potential and disrupts membrane integrity, causing bacterial cell autolysis and DNA release. DNA subsequently promotes biofilm formation and increases antibiotic tolerance to beta-lactams, suggesting that HQNO-dependent cell autolysis is advantageous to the bacterial populations. These data identify both a new programmed cell death system and a novel role for HQNO as a critical inducer of biofilm formation and antibiotic tolerance. This newly identified pathway suggests intriguing mechanistic similarities with the initial mitochondrial-mediated steps of eukaryotic apoptosis.

The expected one-pot multiple functionalization of hydroxyquinolines and quinolones with acylacetylenes (20 mol% KOH, 5 equiv. H2O, MeCN, 55–60 °C), which, according to the previous finding, might involve the addition of OH and NH-functions to the triple bond and insertion of acylacetylenes into the quinoline scaffold, retains mainly on the formation of chalcone-quinoline ensembles in up 99% yield. The higher functionalized quinolines can be obtained in a synthetically acceptable yield, when the above ensembles are treated with the second molecule of acylacetylenes. Thus, the further insertion of second molecule of the acetylenes into the quinoline scaffold occurs as a much slower process indicating a strong adverse substituent effect of the remote chalcone moiety., Graphical abstract Image 1, Highlights • One-pot multiple functionalization of hydroxyquinolines and quinolones by acylacetylenes afforded to chalcone-quinoline ensembles. • The reaction proceeded in a short time with excellent product yields. • Broad scope of the reaction. • Deeper functionalization of primary adducts by second molecule of acylcetylene as well as by reducing the chalcone moiety to allyl alcohol.

Compounds containing the 8-hydroxyquinoline (8-HQ) 1 nucleus exhibit a wide range of biological activities, including antimicrobial, anticancer, and antifungal effects. The chemistry and biology of this group have attracted the attention of chemists, medicinal chemists, and professionals in health sciences. A number of prescribed drugs incorporate this group, and numerous 8-HQ- based molecules can be used to develop potent lead compounds with good efficacy and low toxicity. This review focusses on the recent advances in the synthesis of 8-HQ derivatives with different pharmacological properties, including anticancer, antiviral, and antibacterial activities. For this purpose, recent relevant references were searched in different known databases and search engines, such as MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Cochrane, Scientific Information Database (SID), SciFinder, and Institute for Scientific Information (ISI) Web of Knowledge. This review article provides a literature overview of the various synthetic strategies and biological activities of 8-HQ derivatives and covers the recent related literature. Taken together, compounds containing the 8-HQ moiety have huge therapeutic value and can act as potential building blocks for various pharmacologically active scaffolds. In addition, several described compounds in this review could act leads for the development of drugs against numerous diseases including cancer.

A convenient synthesis of 3-hydroxyquinolines has been described via unprecedented Dakin oxidation of quinoline-3-carboxaldehydes. Subsequently, application of the methodology to a high yielding synthesis of quinoline alkaloid Jineol (1) is reported.

A series of eight alkyl gallium complexes of general formulae [GaMe2(L)] and [Ga(Me)2L] have been synthesised, characterised and their antimicrobial activity against bacteria, cancer cells and Leishmania assessed. All eight complexes are novel, with the solid-state structures of all complexes successfully authenticated by single crystal X-ray diffraction. The dimethyl complexes all adopt a four-coordinate tetrahedral confirmation, while the monomethyl complexes are five-coordinate trigonal bipyramidal. All complexes were screened for their anti-bacterial activity either by solution state diffusion, or a solid-state stab test. The five soluble complexes underwent testing against two differing mammalian cell controls, with excellent selectivity observed against COS-7 cells, with an IC50 range of 88.5 μM to ≥100 μM. Each soluble complex was also tested for their anti-cancer capabilities, with no significant activity observed. Excellent activity was exhibited against the protozoan parasite Leishmania major (strain: V121) in both the promastigote and amastigote forms, with IC50 values ranging from 1.11 μM-13.4 μM for their anti-promastigote activity and % infection values of 3.5% ± 0.65-11.5% ± 0.65 for the more clinically relevant amastigote. Selectivity indices for each were found to be in the ranges of 6.61-64.7, with significant selectivity noted for two of the complexes. At minimum, the gallium complexes show a 3-fold enhancement in activity towards the Leishmaniaamastigotes over the parent quinolinols alone.

There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8‐hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure–activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8‐hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of 4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC50 of

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8μM and 18.0±2.3μM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50values of 0.313±0.008 and 3.72±0.20μM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50of 0.138±0.013μM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4’-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4’-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.

A series of novel β

A series of functionalized 3,4-dihydroquinolinium salts were prepared from the reaction of aryldiazonium salt with alkene in a nitrile solution. Further oxidation yielding either 3-hydroxyquinoline or quinoline products was investigated. A one-pot process from aryldiazonium salts, alkenes and nitriles leading to 3-hydroxyquinolines was also developed. Furthermore, an intramolecular trapping of an N-arylnitrilium ion with a vinyl group at the ortho position leading to 2-substituted quinolines was revealed.

Botulinum neurotoxins (BoNTs) are the most toxic category A biological warfare agents. There is no therapeutics available for BoNT intoxication yet, necessitating the development of a medical countermeasure against these neurotoxins. The discovery of small molecule-based drugs has revolutionized in the last two decades resulting in the identification of several small molecule inhibitors of BoNTs. However, none progressed to clinical trials. 8-Hydroxyquinolines scaffold-based molecules are important ‘privileged structures’ that can be exploited as inhibitors of a diverse range of targets. In this review, our study of recent reports suggests the development of 8-hydroxyquinoline derived molecules as a potential drug may be on the horizon.

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells., Centro de Química Inorgánica

The combination of tools such as time-kill assay with subsequent application of mathematical modeling can clarify the potential of new antimicrobial compounds, since minimal inhibitory concentration (MIC) value does not provide a very detailed characterization of antimicrobial activity. Recently, our group has reported that the 8-hydroxy-5-quinolinesulfonic acid presents relevant antifungal activity. However, its intrinsic acidity could lead to an ionization process, decreasing fungal cell permeability. To overcome this potential problem and enhance activity, the purpose of this study was to synthesize and evaluate a novel series of hybrids between the 8-hydroxyquinoline core and sulfonamide and to prove their potential using broth microdilution method, obtaining the pharmacodynamic parameters of the most active derivatives combining time-kill studies and mathematical modeling and evaluating their toxicity. Compound 5a was the most potent, being active against all the fungal species tested, with low toxicity in normal cells. 5a and 5b have presented important antibacterial activity against Staphylococcus aureus strain. The EC50 values obtained by combination of time-kill studies with mathematical model were similar to those of MIC, which confirms the potential of compounds. In addition, these derivatives are non-irritant molecules with the absence of topical toxicity. Finally, 5a and 5b are promising candidates for treatment of dermatomycosis and candidiasis.

The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate., Viridicatin is a fungal alkaloid. Here, the authors identify and characterize the cyclopenase that catalyzes the last step of its biosynthesis in Aspergillus nidulans, the conversion of cyclopenin to viridicatin, and find that the reaction proceeds via an unusual elimination mechanism.

Background: According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. : Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective. Objective: The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay. Methods: The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3). Results: All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R′= -H) and IV d-1 (R= -CH2-C6H5; R′= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 μM/ml and 0.455 μM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 μM/ml. Conclusion: The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.

In this review, the recent synthetic approaches of amino hexahydroquinolines and their spirocyclic structures were highlighted. The synthetic routes include, two-components, three-components or fourcomponents reactions. The two-component [3+3] atom combination reaction represents the simplest method. It involves Michael addition of the electron rich β-carbon of β-enaminones to the activated double bond of cinnamonitriles followed by cyclization to yield hexahydroquinoline compounds. The bioactivity profiles and SAR studies of these compounds were also reviewed with emphasis to the utility of these substances as antimicrobial, anticancer and antitubercular agents, as well as calcium channel modulators.

Iron overload causes many diseases, while the underlying etiologies of these diseases are unclear. Cell death processes including apoptosis, necroptosis, cyclophilin D-(CypD)-dependent necrosis and a recently described additional form of regulated cell death called ferroptosis, are dependent on iron or iron-dependent reactive oxygen species (ROS). However, whether the accumulation of intracellular iron itself induces ferroptosis or other forms of cell death is largely elusive. In present study, we study the role of intracellular iron overload itself-induced cell death mechanisms by using ferric ammonium citrate (FAC) and a membrane-permeable Ferric 8-hydroxyquinoline complex (Fe-8HQ) respectively. We show that FAC-induced intracellular iron overload causes ferroptosis. We also identify 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitor GSK2334470 as a potent ferroptosis inhibitor. Whereas, Fe-8HQ-induced intracellular iron overload causes unregulated necrosis, but partially activates PARP-1 dependent parthanatos. Interestingly, we identify many phenolic compounds as potent inhibitors of Fe-8HQ-induced cell death. In conclusion, intracellular iron overload-induced cell death form might be dependent on the intracellular iron accumulation rate, newly identified cell death inhibitors in our study that target ferroptosis and unregulated oxidative cell death represent potential therapeutic strategies against iron overload related diseases.

The present study investigates the human monoamine oxidase (MAO) inhibition properties of a series of twelve 2-heteroarylidene-1-tetralone derivatives. Also included are related cyclohexylmethylidene, cyclopentylmethylidene and benzylidene substituted 1-tetralones. These compounds are related to the 2-benzylidene-1-indanone class of compounds which has previously been shown to inhibit the MAOs, with specificity for the MAO-B isoform. The target compounds were synthesised by the Claisen-Schmidt condensation between 7-methoxy-1-tetralone or 1-tetralone, and various aldehydes, under acid (hydrochloric acid) or base (potassium hydroxide) catalysis. The results of the MAO inhibition studies showed that the 2-heteroarylidene-1-tetralone and related derivatives are in most instances more selective inhibitors of the MAO-B isoform compared to MAO-A. (2E)-2-Benzylidene-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one (IC50=0.707 μM) was found to be the most potent MAO-B inhibitor, while the most potent MAO-A inhibitor was (2E)-2-[(2-chloropyridin-3-yl)methylidene]-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one (IC50=1.37 μM). The effect of the heteroaromatic substituent on MAO-B inhibition activity, in decreasing order was found to be: cyclohexyl, phenyl>thiophene>pyridine, furane, pyrrole, cyclopentyl. This study concludes that, although some 2-heteroarylidene-1-tetralone derivatives are good potency MAO inhibitors, in general their inhibition potencies, particularly for MAO-B, are lower than structurally related chalcones and 1-indanone derivatives that were previously studied.

Pseudomonas aeruginosa is a Gram-negative bacterium responsible for a large number of nosocomial infections. The P. aeruginosa respiratory chain contains the ion-pumping NADH:ubiquinone oxidoreductase (NQR). This enzyme couples the transfer of electrons from NADH to ubiquinone to the pumping of sodium ions across the cell membrane, generating a gradient that drives essential cellular processes in many bacteria. In this study, we characterized P. aeruginosa NQR (Pa-NQR) to elucidate its physiologic function. Our analyses reveal that Pa-NQR, in contrast with NQR homologues from other bacterial species, is not a sodium pump, but rather a completely new form of proton pump. Homology modeling and molecular dynamics simulations suggest that cation selectivity could be determined by the exit ion channels. We also show that Pa-NQR is resistant to the inhibitor 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO). HQNO is a quinolone secreted by P. aeruginosa during infection that acts as a quorum sensing agent and also has bactericidal properties against other bacteria. Using comparative analysis and computational modeling of the ubiquinone-binding site, we identified the specific residues that confer resistance toward this inhibitor. In summary, our findings indicate that Pa-NQR is a proton pump rather than a sodium pump and is highly resistant against the P. aeruginosa–produced compound HQNO, suggesting an important role in the adaptation against autotoxicity. These results provide a deep understanding of the metabolic role of NQR in P. aeruginosa and provide insight into the structural factors that determine the functional specialization in this family of respiratory complexes.

Covering: up to 2018 Non-heme iron enzymes are a versatile family of oxygenases that catalyze remarkable types of chemistry. This review highlights the intriguing chemistry of non-heme iron enzymes, especially those utilizing α-ketoglutarate (α-KG) as a co-substrate, in fungal secondary metabolism and aims to summarize how nature diversifies and complexifies natural products.

OBJECTIVE The aim of the study was to describe the effect of frequency of pessary removal on the vaginal microenvironment. METHODS We performed a secondary analysis of a multicenter randomized trial of hydroxyquinoline gel in women presenting for pessary fitting. Patients had vaginal secretions analyzed at baseline, 2 weeks, and 3 months. Patients were stratified by frequency of pessary removal at least once daily, at least once weekly, and less often than once weekly. These groups were compared for prevalence of Lactobacillus predominance (primary outcome), anaerobic predominance, Mobiluncus prominence, vaginal symptoms, and bacterial vaginosis by Nugent criteria, and correction for confounding variables was performed. RESULTS One hundred thirty-seven women were included in this analysis: 34 (25%) removed the pessary daily, 54 (39%) at least weekly, and 49 (36%) less often than once weekly. Women who removed the pessary less often than weekly were older (P < 0.01), using more hormone therapy (P = 0.03), and more likely to have bacterial vaginosis at baseline (P < 0.01). At 2 weeks, the predominance of Lactobacillus in the group removing pessary daily was higher (41% daily vs 24% weekly vs 9% longer, P = 0.03) and this persisted after confounder correction (P < 0.01). Women who removed their pessary less than weekly were more likely to have anaerobic predominance at 3 months (P = 0.04). CONCLUSIONS Women who remove their pessaries less often than once weekly have an increased prevalence of anaerobes at 3 months, but no difference in vaginal symptoms or pessary satisfaction.

There is a general lack of understanding about how communities of bacteria respond to exogenous toxins such as antibiotics. Most of our understanding of community-level stress responses comes from the study of stationary biofilm communities. Although several community behaviors and production of specific biomolecules affecting biofilm development and associated behavior have been described for Pseudomonas aeruginosa and other bacteria, we have little appreciation for the production and dispersal of secreted metabolites within the 2D and 3D spaces they occupy as they colonize, spread, and grow on surfaces. Here we specifically studied the phenotypic responses and spatial variability of alkyl quinolones, including the Pseudomonas quinolone signal (PQS) and members of the alkyl hydroxyquinoline (AQNO) subclass, in P. aeruginosa plate-assay swarming communities. We found that PQS production was not a universal signaling response to antibiotics, as tobramycin elicited an alkyl quinolone response, whereas carbenicillin did not. We also found that PQS and AQNO profiles in response to tobramycin were markedly distinct and influenced these swarms on different spatial scales. At some tobramycin exposures, P. aeruginosa swarms produced alkyl quinolones in the range of 150 μm PQS and 400 μm AQNO that accumulated as aggregates. Our collective findings show that the distribution of alkyl quinolones can vary by several orders of magnitude within the same swarming community. More notably, our results suggest that multiple intercellular signals acting on different spatial scales can be triggered by one common cue.

8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.

Intramolecular asymmetric allylic alkylation reactions of 5- and 7-hydroxyquinoline derivatives were realized by a chiral Ir/NHC catalyst. A series of functionalized cyclic enones were afforded in excellent yields (up to 99%) and high enantioselectivity (up to 97% ee). Theoretical computations revealed that the aromaticity of the two consecutive rings of hydroxyquinoline substrates is significantly weakened. A highly efficient formal synthesis of (−)-gephyrotoxin was accomplished based on this method.

Ru(arene) compounds have many desirable features making them promising candidates for further development in anticancer drug research. While a lot of emphasis has been placed on the modification of the ancillary ligands, there are not many examples of arene ligands bearing functional groups. Herein, we report the preparation of [Ru(arene)(8-oxyquinolinato)Cl] complexes with the arene being a protected form of the amino acid L-phenylalanine and 8-oxyquinolinato ligand substituted with halogens. With this approach we aimed to alter the pharmacological properties of the complexes and address issues with the aqueous solubility of the analogous p-cymene complexes. The complexes were shown to be stable in DMSO and water and reacted readily with L-histidine and 9-ethylguanine as protein and DNA models, respectively. Assaying the antiproliferative activity in cancer cells gave IC50 values in the low μM range. While the lipophilicity of the p-cymene analogues correlated well with their in vitro cytotoxicity, the potency of the complexes with the L-phenylalanine-derived arene was independent of lipophilicity.

Chronic gut inflammation disposes to an increased risk of colitis-associated cancer. Chemoprevention is an attractive complementary strategy. We aimed to evaluate the chemopreventive effects of M10, a novel derivative of Myricetin, in the murine azoxymethane/dextran sodium sulfate model. Oral administration of M10 at 50-100 mg/kg once a day for consecutive 12 weeks significantly prevented ulcerative colitis (UC) and colorectal tumor. Pathological analysis of intestines showed that M10 reduced the degree of chronic inflammation and prevented the progression of colorectal tumorigenesis. Flow cytometry analysis of the immunocytes isolated from intraepithelial and lamina propria showed that M10 prevented the infiltration of myeloid-derived suppressor cells and increased CD8+T and CD4+T cells in colorectal tissues. Enzyme-linked immunosorbent analysis revealed the reduction of pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor/macrophage colony-stimulating factor, IL-6 and TNF-α in colonic mucosa. Western blot assay also showed M10 prevention of the NF-κB/IL-6/STAT3 pathways and the biomarkers of inflammation and colorectal tumorigenesis. Electron microscopy analysis revealed that M10 prevent robust endoplasmic reticulum (ER) stress-induced autophagy in inflamed colonic mucosal cells. In conclusion, oral administration of Myricetin derivative M10 exerts chemoprevention of UC and colorectal tumor in mice. The mechanism of chemoprevention is associated with the reduction of biomarkers of chronic inflammation and proliferation through attenuating robust ER stress in inflamed colonic mucosal cells. M10 exerts chemoprevention activity without evidence of toxicity in mice. These results justify further evaluation of M10 in clinical trials. M10 could develop a promising regimen in the chemoprevention of colitis and colorectal cancer.

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.

The propensity for differentiation varies substantially across human pluripotent stem cell (hPSC) lines, greatly restricting the use of hPSCs for cell replacement therapy or disease modeling. Here, we investigate the underlying mechanisms and demonstrate that activation of the retinoblastoma (Rb) pathway in a transient manner is important for differentiation. In prior work, we demonstrated that pre-treating hPSCs with dimethylsulfoxide (DMSO) before directed differentiation enhanced differentiation potential across all three germ layers. Here, we show that exposure to DMSO improves the efficiency of hPSC differentiation through Rb and by repressing downstream E2F-target genes. While transient inactivation of the Rb family members (including Rb, p107, and p130) suppresses DMSO’s capacity to enhance differentiation across all germ layers, transient expression of a constitutively active (non-phosphorylatable) form of Rb increases the differentiation efficiency similar to DMSO. Inhibition of downstream targets of Rb, such as E2F signaling, also promotes differentiation of hPSCs. More generally, we demonstrate that the duration of Rb activation plays an important role in regulating differentiation capacity.

This article belongs to the Special Issue Stereogenic Centers., Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of β-isocupreidine catalyst are reported. The moderate, but promising, enantioselectivity observed (40–54% ee), opens the door to a new area of research for the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore, our research represents a pivotal example in this field which remains still unexplored., This research was funded by Ministerio de Economía, Industria y Competitividad [CTQ2017-88091-P], Universidad de Zaragoza [JIUZ-2017-CIE-05] and Gobierno de Aragón-Fondo Social Europeo [Research Group E07_17R].

Spatio-temporal release of biologically relevant small molecules provides exquisite control over the activation of receptors and signaling pathways. This can be accomplished via a photochemical reaction that releases the desired small molecule in response to irradiation with light. A series of biologically-relevant signaling molecules (serotonin, octopamine, capsaicin, N-vanillyl-nonanoylamide, estradiol, and tyrosine) that contain a phenol moiety were conjugated to the 8-bromo-7-hydroxyquinolinyl (BHQ) or 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting groups (PPGs). The CyHQ caged compounds proved sensitive toward 1PE and 2PE processes with quantum efficiencies of 0.2-0.4 upon irradiation at 365 nm and two-photon action cross sections of 0.15-0.31 GM when irradiated at 740 nm. All but one BHQ caged compound, BHQ-estradiol, were found to be sensitive to photolysis through 1PE and 2PE with quantum efficiencies of 0.30-0.40 and two photon cross sections of 0.40-0.60 GM. Instead of releasing estradiol, BHQ-estradiol underwent debromination.

This study investigated the antibacterial activity of the plant alkaloid tomatidine (TO) against Staphylococcus aureus grown in the presence of Pseudomonas aeruginosa . Since the P. aeruginosa exoproduct 4-hydroxy-2-heptylquinoline- N -oxide (HQNO) is known to cause a respiratory deficiency in S. aureus and respiratory-deficient S. aureus are known to be hypersensitive to TO, we assessed kill kinetics of TO (8 μg/ml) against S. aureus in coculture with P. aeruginosa . Kill kinetics were also assessed using P. aeruginosa mutants deficient in the production of different exoproducts and quorum sensing-related compounds. After 24 h in coculture, TO increased the killing of S. aureus by 3.4 log 10 CFU/ml in comparison to that observed in a coculture without TO. The effect of TO was abolished when S. aureus was in coculture with the lasR rhlR , pqsA , pqsL , or lasA mutant of P. aeruginosa . The bactericidal effect of TO against S. aureus in coculture with the pqsL mutant was restored by supplemental HQNO. In an S. aureus monoculture, the combination of HQNO and TO was bacteriostatic, indicating that the pqsL mutant produced an additional factor required for the bactericidal effect. The bactericidal activity of TO was also observed against a tobramycin-resistant methicillin-resistant S. aureus (MRSA) in coculture with P. aeruginosa , and the addition of tobramycin significantly suppressed the growth of both microorganisms. TO shows a strong bactericidal effect against S. aureus when cocultured with P. aeruginosa . The combination of TO and tobramycin may represent a new treatment approach for cystic fibrosis patients frequently cocolonized by MRSA and P. aeruginosa .

Ethyl 3-(2,4-dioxocyclohexyl)propanoate has been explored as a precursor for the synthesis of N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones following conventional protecvtion, selective amidation, and deprotective-cyclization approaches. Moreover, a facile process for the selective dehydrogenative aromatization of these diones was developed to afford the corresponding N-substituted 3,4-dihydro-7-hydroxyquinolin-2(1H)-ones and N-substituted 7-hydroxyquinolin-2(1H)-ones under mild conditions.

Podocyte injury and loss mark an early step in the pathogenesis of various glomerular diseases, making these cells excellent targets for therapeutics. However, cell–based high–throughput screening assays for the rational development of podocyte-directed therapeutics are currently lacking. Here, we describe a novel high–content screening–based phenotypic assay that analyzes thousands of podocytes per assay condition in 96-well plates to quantitatively measure dose-dependent changes in multiple cellular features. Our assay consistently produced a Z′ value >0.44, making it suitable for compound screening. On screening with >2100 pharmacologically active agents, we identified 24 small molecules that protected podocytes against injury in vitro (1% hit rate). Among the identified hits, we confirmed an β1-integrin agonist, pyrintegrin, as a podocyte-protective agent. Treatment with pyrintegrin prevented damage-induced decreases in F-actin stress fibers, focal adhesions, and active β1-integrin levels in cultured cells. In vivo, administration of pyrintegrin protected mice from LPS–induced podocyte foot process effacement and proteinuria. Analysis of the murine glomeruli showed that LPS administration reduced the levels of active β1 integrin in the podocytes, which was prevented by cotreatment with pyrintegrin. In rats, pyrintegrin reduced peak proteinuria caused by puromycin aminonucleoside–induced nephropathy. Our findings identify pyrintegrin as a potential therapeutic candidate and show the use of podocyte–based screening assays for identifying novel therapeutics for proteinuric kidney diseases.

Three novel 5-(N-substituted-anilino)-8-benzyloxyquinoline derivatives were efficiently synthesized via Hartwig–Buchwald amination reaction. The new 5-(N-substituted-anilino)-8-benzyloxyquinolines were reduced for 1–3 h to give the corresponding 5-(N-substituted-anilino)-8-hydroxyquinolines. Extending the reduction reaction time to 7 h afforded the corresponding 1,2,3,4-tetrahydro-8-hydroxyquinoline derivatives.

The epigenetic modification of vascular smooth muscle cell (VSMC) phenotypic switching, proliferation, migration, apoptosis and extracellular matrix synthesis is known to occur in atherosclerosis. The aim of the present study was to investigate the effects of IOX1, a Jumonji domain-containing 2A (JMJD2A) inhibitor, on regulation of the cell cycle in angiotensin II (Ang II)-stimulated VSMCs and to elucidate the possible mechanisms involved. The proliferation and migration of the Ang II-stimulated VSMCs in the presence or absence of IOX1 were evaluated in vitro. Flow cytometric analysis was used to determine the effects of IOX1 on cell cycle progression. RT-qPCR and western blot analysis were carried out to measure the expression levels of cell cycle-related genes. The trimethylation of histone H3 lysine 9 (H3K9me3) at the promoters of these genes was detected by chromatin immunoprecipitation (ChIP) assay. We confirmed that the JMJD2A levels were increased, whereas the H3K9me3 levels were decreased in the Ang II-stimulated VSMCs. The inhibition of JMJD2A by IOX1 suppressed the Ang II-induced cell proliferation, migration and cell cycle progression by inhibiting cyclin D1 expression and increasing p21 expression. The underlying mechanisms were related to the restoration of the H3K9me3 levels at the promoters of these genes. In conclusion, the findings of our study indicate that IOX1 exerts its anti-proliferative and anti-migratory effects by regulating the expression of the cell cycle-related proteins, cyclin D1 and p21.

Quinoline, a recalcitrant heterocyclic compound, is biodegraded by a series of reactions that begin with mono-oxygenations, which require an intracellular electron donor. Photolysis of quinoline can generate readily biodegradable products, such as oxalate, whose bio-oxidation can generate endogenous electron donors that ought to accelerate quinoline biodegradation and, ultimately, mineralization. To test this hypothesis, we compared three protocols for the biodegradation of quinoline: direct biodegradation (B), biodegradation after photolysis of 1 h (P1h+B) or 2 h (P2h+B), and biodegradation by adding oxalate commensurate to the amount generated from photolysis of 1 h (O1+B) or 2 h (O2+B). The experimental results show that P1h+B and P2h+B accelerated quinoline biodegradation by 19% and 50%, respectively, compared to B. Protocols O1+B and O2+B also gave 19% and 50% increases, respectively. During quinoline biodegradation, its first intermediate, 2-hydroxyquinoline, accumulated gradually in parallel to quinoline loss but declined once quinoline was depleted. Mono-oxygenation of 2-hydroxyquinoline competed with mono-oxygenation of quinoline, but the inhibition was relieved when extra electrons donors were added from oxalate, whether formed by UV photolysis or added exogenously. Rapid oxalate oxidation stimulated both mono-oxygenations, which accelerated the overall quinoline oxidation that provided the bulk of the electron donor.