Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 141
Filter
1.
J Inorg Biochem ; 228: 111697, 2022 03.
Article in English | MEDLINE | ID: mdl-34999425

ABSTRACT

In this study, four hybrid organic-inorganic compounds (8-H2Q)2[PdCl4] (1), (H2ClQ)2[PdCl4] (2), (H2NQ)2[PdCl4] (3) and (H2MeQ)2[PdCl4]·2H2O (4) (where 8-H2Q = 8-hydroxyquinolinium, H2ClQ = 5-chloro-8-hydroxyquinolinium, H2NQ = 5-nitro-8-hydroxyquinolinium and H2MeQ = 2-methyl-8-hydroxyquinolinium) were synthesized through organic cation modulation. Single-crystal X-ray structure analysis of compounds 1 and 3 indicates that their structures are planar and consist of [PdCl4]2- anions and 8-H2Q or H2NQ cations, respectively. Both ionic components are held together through ionic interactions and hydrogen bonds forming infinite chains linked through π-π interactions to form 2D structures. Furthermore, NMR spectroscopy, UV-Vis spectroscopy, elemental analysis, and FT-IR spectroscopy were used to explore the synthesized compounds. The DNA interaction, antimicrobial activity, antiproliferative activity, and radical scavenging effect of the compounds were evaluated. The hybrid compounds and their free ligands can interact with the calf thymus DNA via an intercalation mode involving the insertion of the aromatic chromophore between the base pairs of DNA; compound 1 has the highest binding affinity. Moreover, they have high antimicrobial efficacy against the tested 14 strains of microorganisms with minimum inhibitory concentration values ranging from <1.95 to 250 µg/mL. The antiproliferative activity of the compounds was investigated against three different cancer cell lines, and their selectivity was verified on mesenchymal stem cells. Compounds 1 and 2 displayed selective and high cytotoxicity against human lung and breast cancer cells and showed moderate cytotoxicity against colon cancer cells. Accordingly, they might be auspicious candidates for future pharmacological investigations in lung and breast cancer research.


Subject(s)
Coordination Complexes/chemistry , Hydroxyquinolines/chemistry , Palladium/chemistry , Quinolinium Compounds/chemistry , A549 Cells , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Chelating Agents/chemistry , Crystallography, X-Ray/methods , DNA/chemistry , Free Radical Scavengers/chemistry , HCT116 Cells , Humans , Hydroxyquinolines/chemical synthesis , Ligands , Magnetic Resonance Spectroscopy/methods , Microbial Sensitivity Tests/methods , Molecular Structure , Quinolinium Compounds/chemical synthesis , Reactive Oxygen Species/metabolism
2.
Chem Biol Drug Des ; 98(5): 894-902, 2021 11.
Article in English | MEDLINE | ID: mdl-34453501

ABSTRACT

Catalyzed peroxidation of unsaturated lipid in animals and plants intimately is linked to the activity of 15-Lipoxygenase enzymes. Lipoxygenases (LOXs) are well known to play an important role in many acute and chronic syndromes such as inflammation, asthma, cancer, and allergy. In this study, a series of mono prenyloxycarbostyrils were synthesized and evaluated as potential inhibitors of soybean 15-Lipoxygenase (SLO) and their inhibitory potencies were compared to mono prenyloxycoumarins which had been reported in the previous works. The synthetic compounds inhibit lipoxygenase enzyme by competitive mechanism like the prenyloxy coumarins. The results showed that position and length of the prenyl moiety play the important role in lipoxygenase inhibitory activity. Among all of the synthetic compounds (coumarin and carbostyril derivatives), 5-farnesyloxycoumarin and 8-farnesyloxycarbostyril demonstrated the best inhibitory activity by IC50  values of 1.1 µM and 0.53 µM, respectively.


Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Hydroxyquinolines/chemical synthesis , Lipoxygenase Inhibitors/chemical synthesis , Quinolones/chemical synthesis , Biphenyl Compounds/chemistry , Coumarins/chemistry , Humans , Hydroxyquinolines/pharmacology , Lipoxygenase Inhibitors/pharmacology , Picrates/chemistry , Quinolones/pharmacology , Glycine max/enzymology , Structure-Activity Relationship
3.
Chem Pharm Bull (Tokyo) ; 69(6): 557-563, 2021.
Article in English | MEDLINE | ID: mdl-34078802

ABSTRACT

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.


Subject(s)
Caenorhabditis elegans/drug effects , Hydroxyquinolines/pharmacology , Spermatozoa/drug effects , Animals , Caenorhabditis elegans/metabolism , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/chemistry , Male , Mice , Mice, Inbred ICR , Molecular Structure , Spermatozoa/metabolism
4.
J Biol Chem ; 296: 100223, 2021.
Article in English | MEDLINE | ID: mdl-33449875

ABSTRACT

Cytochrome P450 (P450) 3A4 is the enzyme most involved in the metabolism of drugs and can also oxidize numerous steroids. This enzyme is also involved in one-half of pharmacokinetic drug-drug interactions, but details of the exact mechanisms of P450 3A4 inhibition are still unclear in many cases. Ketoconazole, clotrimazole, ritonavir, indinavir, and itraconazole are strong inhibitors; analysis of the kinetics of reversal of inhibition with the model substrate 7-benzoyl quinoline showed lag phases in several cases, consistent with multiple structures of P450 3A4 inhibitor complexes. Lags in the onset of inhibition were observed when inhibitors were added to P450 3A4 in 7-benzoyl quinoline O-debenzylation reactions, and similar patterns were observed for inhibition of testosterone 6ß-hydroxylation by ritonavir and indinavir. Upon mixing with inhibitors, P450 3A4 showed rapid binding as judged by a spectral shift with at least partial high-spin iron character, followed by a slower conversion to a low-spin iron-nitrogen complex. The changes were best described by two intermediate complexes, one being a partial high-spin form and the second another intermediate, with half-lives of seconds. The kinetics could be modeled in a system involving initial loose binding of inhibitor, followed by a slow step leading to a tighter complex on a multisecond time scale. Although some more complex possibilities cannot be dismissed, these results describe a system in which conformationally distinct forms of P450 3A4 bind inhibitors rapidly and two distinct P450-inhibitor complexes exist en route to the final enzyme-inhibitor complex with full inhibitory activity.


Subject(s)
Clotrimazole/pharmacology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/chemistry , Indinavir/pharmacology , Itraconazole/pharmacology , Ketoconazole/pharmacology , Ritonavir/pharmacology , Steroid Hydroxylases/antagonists & inhibitors , Animals , Biocatalysis , Cloning, Molecular , Clotrimazole/chemistry , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/chemistry , Enzyme Assays , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/metabolism , Indinavir/chemistry , Itraconazole/chemistry , Ketoconazole/chemistry , Kinetics , Rats , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Ritonavir/chemistry , Steroid Hydroxylases/chemistry , Steroid Hydroxylases/genetics , Steroid Hydroxylases/metabolism
5.
Sci Rep ; 10(1): 21691, 2020 12 10.
Article in English | MEDLINE | ID: mdl-33303858

ABSTRACT

A novel, expedient and effective methodology for the synthesis of distinctly substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline systems has been developed with a new synthetic platform. This process includes ammonium acetate-mediated cyclocondensation reactions of 3-oxo-2-arylhydrazonopropanals with benzosuberone and tetralone precursors, respectively, using the high-pressure Q-tube reactor, which has been found to be superior to both conventional heating and microwave irradiation. The novel protocol benefits from its high atom efficiency, economy, ease of workup, broad substrate scope and is also applicable to gram-scale synthesis. To identify and confirm the newly synthesized targeted compounds, the X-ray single-crystal as well as all possible spectroscopic methods were utilized. The cytotoxicity of the newly synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j and 5,6-dihydrobenzo-[h]quinolines derivatives 6a-e were preliminary examined toward three cell lines of human cancer; lung cancer (A549), breast cancer (MCF-7) and colon cancer (HCT-116), by applying the MTT colorimetric assay. The achieved results reflected the promising profile of the prepared compounds in this study against cancer cells and have shown that members from the synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j exhibited promising cytotoxicity's against MCF-7, and A549 cancer cells respectively, while the HCT-116 (colon) cancer cells were inhibited by certain examples of 5,6-dihydrobenzo[h]quinoline derivatives 6c,d. These promising results could serve as a good primary base for further research into the design of anticancer drugs.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/pharmacology , Pressure , Pyridines/chemical synthesis , Pyridines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Colonic Neoplasms/pathology , Crystallography, X-Ray , Cyclization , Drug Design , Heterocyclic Compounds/chemistry , Humans , Hydroxyquinolines/chemistry , Pyridines/chemistry , Spectrum Analysis
6.
Molecules ; 25(22)2020 Nov 20.
Article in English | MEDLINE | ID: mdl-33233747

ABSTRACT

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.


Subject(s)
Chemistry Techniques, Synthetic , Hydroxyquinolines/chemical synthesis , Quinolones/chemical synthesis , Catalysis , Chemistry Techniques, Synthetic/methods , Chemistry Techniques, Synthetic/trends , Hydroxyquinolines/chemistry , Metals/chemistry , Molecular Structure , Quinolones/chemistry
7.
ACS Chem Biol ; 15(9): 2516-2528, 2020 09 18.
Article in English | MEDLINE | ID: mdl-32865973

ABSTRACT

The chemosensory system of any animal relies on a vast array of detectors tuned to distinct chemical cues. Odorant receptors and the ion channels of the TRP family are all uniquely expressed in olfactory tissues in a species-specific manner. Great effort has been made to characterize the molecular and pharmacological properties of these proteins. Nevertheless, most of the natural ligands are highly hydrophobic molecules that are not amenable to controlled delivery. We sought to develop photoreleasable, biologically inactive odorants that could be delivered to the target receptor or ion channel and effectively activated by a short light pulse. Chemically distinct ligands eugenol, benzaldehyde, 2-phenethylamine, ethanethiol, butane-1-thiol, and 2,2-dimethylethane-1-thiol were modified by covalently attaching the photoremovable protecting group (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ). The CyHQ derivatives were shown to release the active odorant upon illumination with 365 and 405 nm light. We characterized their bioactivity by measuring activation of recombinant TRPV1 and TRPA1 ion channels expressed in HEK 293 cells and the electroolfactogram (EOG) response from intact mouse olfactory epithelium (OE). Illumination with 405 nm light was sufficient to robustly activate TRP channels within milliseconds of the light pulse. Photoactivation of channels was superior to activation by conventional bath application of the ligands. Photolysis of the CyHQ-protected odorants efficiently activated an EOG response in a dose-dependent manner with kinetics similar to that evoked by the vaporized odorant amyl acetate (AAc). We conclude that CyHQ-based, photoreleasable odorants can be successfully implemented in chemosensory research.


Subject(s)
Benzaldehydes/pharmacology , Eugenol/pharmacology , Hydroxyquinolines/chemistry , Odorants , Phenethylamines/pharmacology , Sulfhydryl Compounds/pharmacology , Animals , Benzaldehydes/chemical synthesis , Eugenol/chemical synthesis , Female , HEK293 Cells , Humans , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/radiation effects , Male , Mice , Olfactory Mucosa/drug effects , Phenethylamines/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , TRPA1 Cation Channel/metabolism , TRPV Cation Channels/metabolism , Ultraviolet Rays
8.
Molecules ; 24(23)2019 Nov 23.
Article in English | MEDLINE | ID: mdl-31771153

ABSTRACT

Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.


Subject(s)
Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/chemistry , Oxyquinoline/analogs & derivatives , Cell Line, Tumor , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Hydroxyquinolines/chemistry , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Membrane Potential, Mitochondrial/drug effects , Oxidative Stress/drug effects , Protein Stability/drug effects , Quinidine/chemistry , Quinine/chemistry , Stereoisomerism
9.
Drug Dev Res ; 80(5): 566-572, 2019 08.
Article in English | MEDLINE | ID: mdl-30893501

ABSTRACT

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 <5 µM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC50 of <100 µM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8-hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.


Subject(s)
Antitubercular Agents/chemical synthesis , Hydroxyquinolines/chemical synthesis , Mycobacterium tuberculosis/growth & development , Oxyquinoline/analogs & derivatives , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Chlorocebus aethiops , Hep G2 Cells , Humans , Hydroxyquinolines/chemistry , Hydroxyquinolines/pharmacology , Microbial Sensitivity Tests , Microbial Viability/drug effects , Molecular Structure , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Vero Cells
10.
Anticancer Agents Med Chem ; 19(7): 875-915, 2019.
Article in English | MEDLINE | ID: mdl-30706793

ABSTRACT

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 ß-carbon of ß-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.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Bacteria/drug effects , Hydroxyquinolines/pharmacology , Neoplasms/drug therapy , Spiro Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Humans , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/chemistry , Spiro Compounds/chemistry , Structure-Activity Relationship
11.
Bioorg Med Chem ; 27(12): 2306-2314, 2019 06 15.
Article in English | MEDLINE | ID: mdl-30392952

ABSTRACT

A series of novel ß2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent ß2-adrenoceptor agonistic effects and high ß2/ß1-selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.


Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Bronchodilator Agents/pharmacology , Ethanolamines/pharmacology , Hydroxyquinolines/pharmacology , Adrenergic beta-2 Receptor Agonists/chemical synthesis , Adrenergic beta-2 Receptor Agonists/metabolism , Animals , Binding Sites , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/metabolism , Drug Design , Ethanolamines/chemical synthesis , Ethanolamines/metabolism , Guinea Pigs , HEK293 Cells , Humans , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/metabolism , Male , Molecular Docking Simulation , Receptors, Adrenergic, beta-2/chemistry , Receptors, Adrenergic, beta-2/metabolism , Trachea/drug effects
12.
ChemMedChem ; 13(5): 422-430, 2018 03 06.
Article in English | MEDLINE | ID: mdl-29334428

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Hydroxamic Acids/pharmacology , Hydroxyquinolines/pharmacology , Macrophages/drug effects , Metalloproteases/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/chemistry , Kinetics , Macrophages/microbiology , Metalloproteases/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure
13.
Talanta ; 179: 326-330, 2018 Mar 01.
Article in English | MEDLINE | ID: mdl-29310239

ABSTRACT

Developing fluorescent probes to image thiols in the living system may provide powerful tools to study the functions of thiol-containing biological molecules. In this study, we report the design and evaluation of a novel turn-on fluorescent probe NQNO for selective detection of thiols in living cells. By introducing an ortho-aldehyde group to NNO, a conventional compound representing a class of thiol-imaging strategy, we obtained NQNO with enhanced selectivity for thiols over the major interferent hydrogen sulfide (H2S). NQNO could be applied in phosphate-buffered saline (PBS), where the efficacy of NNO was usually weakened. Notably, NQNO demonstrated solid performance in imaging endogenous thiols in living cells without exerting cytotoxicity. In summary, NQNO has the potential to serve as a safe, sensitive and effective fluorescent probe for thiol imaging in biological systems.


Subject(s)
Aldehydes/chemistry , Cysteine/analysis , Fluorescent Dyes/chemical synthesis , Glutathione/analysis , Homocysteine/analysis , Hydroxyquinolines/chemical synthesis , Optical Imaging/methods , Buffers , Fluorescent Dyes/chemistry , HeLa Cells , Humans , Hydrogen Sulfide/chemistry , Hydroxyquinolines/chemistry
14.
Nat Protoc ; 12(3): 461-471, 2017 03.
Article in English | MEDLINE | ID: mdl-28151463

ABSTRACT

Magnesium plays a crucial role in many physiological functions and pathological states. Therefore, the evolution of specific and sensitive tools capable of detecting and quantifying this element in cells is a very desirable goal in biological and biomedical research. We developed a Mg2+-selective fluorescent dye that can be used to selectively detect and quantify the total magnesium pool in a number of cells that is two orders of magnitude smaller than that required by flame atomic absorption spectroscopy (F-AAS), the reference analytical method for the assessment of cellular total metal content. This protocol reports itemized steps for the synthesis of the fluorescent dye based on diaza-18-crown-6-hydroxyquinoline (DCHQ5). We also describe its application in the quantification of total intracellular magnesium in mammalian cells and the detection of this ion in vivo by confocal microscopy. The use of in vivo confocal microscopy enables the quantification of magnesium in different cellular compartments. As an example of the sensitivity of DCHQ5, we studied the involvement of Mg2+ in multidrug resistance in human colon adenocarcinoma cells sensitive (LoVo-S) and resistant (LoVo-R) to doxorubicin, and found that the concentration was higher in LoVo-R cells. The time frame for DCHQ5 synthesis is 1-2 d, whereas the use of this dye for total intracellular magnesium quantification takes 2.5 h and for ion bioimaging it takes 1-2 h.


Subject(s)
Chemistry Techniques, Synthetic/methods , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Intracellular Space/metabolism , Magnesium/metabolism , Microscopy, Fluorescence , Cell Line, Tumor , Fluorescent Dyes/chemistry , Humans , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/chemistry , Hydroxyquinolines/metabolism
15.
Int J Mol Sci ; 17(10)2016 Oct 22.
Article in English | MEDLINE | ID: mdl-27782083

ABSTRACT

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.


Subject(s)
Drug Design , Hydroxyquinolines/chemistry , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase Inhibitors/chemistry , Naphthyridines/chemistry , Enzyme Assays , Humans , Hydroxyquinolines/chemical synthesis , Kinetics , Matrix Metalloproteinase Inhibitors/chemical synthesis , Molecular Docking Simulation , Molecular Dynamics Simulation , Naphthyridines/chemical synthesis , Protein Binding , Protein Domains , Protein Structure, Secondary , Recombinant Proteins/chemistry , Structure-Activity Relationship , Zinc/chemistry
16.
Chem Asian J ; 11(17): 2436-42, 2016 Sep 06.
Article in English | MEDLINE | ID: mdl-27432795

ABSTRACT

Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α-synuclein. This paper presents a new cyclodextrin-8-hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3-functionalized with 8-hydroxyquinoline as copper(II) chelators and inhibitors of copper-induced synuclein aggregation. The encouraging results establish the potential of cyclodextrin-8-hydroxyquinoline conjugates as chelators for the control of copper toxicity.


Subject(s)
Copper/chemistry , Cyclodextrins/chemistry , Hydroxyquinolines/chemistry , Hydroxyquinolines/pharmacology , Protein Aggregation, Pathological/prevention & control , alpha-Synuclein/antagonists & inhibitors , Antitoxins/pharmacology , Binding Sites , Cyclodextrins/chemical synthesis , Cyclodextrins/pharmacology , Hydroxyquinolines/chemical synthesis , alpha-Synuclein/chemistry
17.
Angew Chem Int Ed Engl ; 55(24): 6988-91, 2016 06 06.
Article in English | MEDLINE | ID: mdl-27097759

ABSTRACT

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.


Subject(s)
Aza Compounds/chemistry , Benzene Derivatives/chemistry , Heterocyclic Compounds/chemical synthesis , Hydroxyquinolines/chemical synthesis , Xylenes/chemistry , Cycloaddition Reaction , Heterocyclic Compounds/chemistry , Hydroxyquinolines/chemistry , Molecular Structure , Photochemical Processes , Stereoisomerism
18.
Arch Pharm (Weinheim) ; 349(5): 327-41, 2016 May.
Article in English | MEDLINE | ID: mdl-27027880

ABSTRACT

Copper and zinc have been found to contribute to the burden of amyloid-ß (Aß) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aß peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aß imaging agent to build a new type of multi-target modulators of Aß aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aß aggregations and significant disassembly of metal-mediated Aß aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.


Subject(s)
Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Hydroxyquinolines/chemistry , Hydroxyquinolines/therapeutic use , Protein Aggregation, Pathological/drug therapy , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/ultrastructure , Chelating Agents/chemical synthesis , Chelating Agents/pharmacology , Chelating Agents/therapeutic use , Clioquinol/analogs & derivatives , Clioquinol/chemistry , Clioquinol/pharmacology , Clioquinol/therapeutic use , Copper/adverse effects , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/pharmacology , Structure-Activity Relationship , Zinc/adverse effects
19.
Mol Divers ; 20(1): 29-40, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26537729

ABSTRACT

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.


Subject(s)
Hydroxyquinolines/chemical synthesis , Propionates/chemistry , Hydroxyquinolines/chemistry , Microwaves , Molecular Structure
20.
Dalton Trans ; 44(48): 20913-25, 2015 Dec 28.
Article in English | MEDLINE | ID: mdl-26575390

ABSTRACT

Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using (77)Se, (1)H and (13)C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aß. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aß aggregation, and an ability to disassemble preformed self- and metal-induced Aß aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg(-1). Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.


Subject(s)
Amyloid beta-Peptides/chemistry , Antioxidants/chemistry , Biocompatible Materials/chemistry , Hydroxyquinolines/chemistry , Metals/chemistry , Organoselenium Compounds/chemistry , Selenium/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/therapeutic use , Azoles/chemistry , Biocompatible Materials/metabolism , Blood-Brain Barrier/metabolism , Catalysis , Chelating Agents/chemistry , Clioquinol/chemistry , Glutathione Peroxidase/chemistry , Glutathione Peroxidase/metabolism , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/therapeutic use , Isoindoles , Magnetic Resonance Spectroscopy , Mice , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/therapeutic use
SELECTION OF CITATIONS
SEARCH DETAIL
...