ABSTRACT
Monitoring the microenvironment within specific cellular regions is crucial for a comprehensive understanding of life events. Fluorescent probes working in different ranges of pH regions have been developed for the local imaging of different pH environments. Especially, rhodamine-based fluorescent pH probes have been of great interest due to their ON/OFF fluorescence depending on the spirolactam ring's opening/closure. By introducing the N-alkyl-hydroxamic acid instead of the alkyl amines in the spirolactam of rhodamine, we were able to tune the pH range where the ring opening and closing of the spirolactam occurs. This six-membered cyclic hydroxamate spirolactam ring of rhodamine B proved to be highly fluorescent in acidic pH environments. In addition, we could monitor pH changes of lysosomes in live cells and zebrafish.
Subject(s)
Fluorescent Dyes , Zebrafish , Animals , Hydrogen-Ion Concentration , Rhodamines , LysosomesABSTRACT
Rhodamine hydrazides and hydroxamates derived from hydrazines and hydroxylamines have been applied as fluorescent chemosensors. Reaction-based irreversible probes based on the specific chemical reactions of reactive target species have been developed and applied in bio-imaging studies. The strong chelation frames provided by the rhodamine hydrazides and hydroxamates have been utilized for the monitoring of metal ions, amino acids, and reactive acid derivatives. This Personal Account focuses on our perspective of developing fluorescent probes based on rhodamine hydrazides and hydroxamates.
ABSTRACT
A novel molecular scaffold, dihydropyridothienopyrimidin-4,9-dione, was synthesized from benzylamine or p-methoxybenzylamine in six steps involving successive ring closure to form a fused ring system composed of dihydropyridone, thiophene and pyrimidone. The pharmacological versatility of the dihydropyridothenopyrimidin-4,9-dione scaffold was demonstrated by inhibitory activity against metabotropic glutamate receptor subtype 1 (mGluR1), which shows that the title compounds can serve as an interesting scaffold for the discovery of potential bioactive molecules for the treatment of human diseases.
Subject(s)
Pyrimidines/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Benzylamines/chemistry , Humans , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacologyABSTRACT
5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2'-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1-8 showed the best binding affinity with a Ki value of 8.69nM and it was verified as a novel antagonist according to functional assays. The compound 1-8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1-8 exhibited an antidepressant effect at a dose of 25mg/kg in the forced swimming test in mice and showed a U-shaped dose-response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone.
Subject(s)
Amides/pharmacology , Antidepressive Agents/pharmacology , Depression/drug therapy , Piperazines/pharmacology , Receptors, Serotonin/metabolism , Amides/administration & dosage , Amides/chemistry , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemistry , HEK293 Cells , Humans , Injections, Intraperitoneal , Male , Mice , Mice, Inbred ICR , Piperazines/administration & dosage , Piperazines/chemistry , SwimmingABSTRACT
It has been reported that 5-HT(7) receptors are promising targets of depression and neuropathic pain. 5-HT(7) receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT(7) modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT(7) receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT(7) receptor with K(i) values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT(7) receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH(3) substituents within the arylpiperazine and the other for biphenyl methoxy group.
Subject(s)
Biphenyl Compounds/pharmacology , Drug Discovery , Piperazines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Binding Sites/drug effects , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Ligands , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
We describe fluorescent probes to detect formaldehyde (FA) in aqueous solutions and cells. The probes rapidly respond to FA in aqueous solutions and have great selectivity toward FA over other biologically relevant analytes. The results of cell studies reveal that probe 1 can be utilized to monitor endogenous and exogenous FA in live cells.
ABSTRACT
We report the stereocontrolled synthesis of 1,6-diazecanes via a tandem aza-Prins type reaction of N-acyliminium ions with allylsilanes. It involves an aza-Prins type dimerization and cyclization in a single-step operation. This reaction represents the first example of 10-membered N-heterocycle synthesis using an aza-Prins reaction. Also, the interesting formation of an unusual tetracyclic compound through further cyclization of 1,6-diazecane and bicyclic compounds by the intramolecular cyclization of linear allylsilane are described. This tandem aza-Prins protocol provides a new synthetic strategy for the direct synthesis of medium-sized nitrogen heterocycles.
Subject(s)
Bridged Bicyclo Compounds , Cyclization , Molecular Structure , Dimerization , StereoisomerismABSTRACT
The synthesis of a novel series of aminoquinazoline derivatives 1a-r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC(50)=0.006 µM) and good selectivity over HS27 fibroblast cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Chromones/chemical synthesis , Quinazolines/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Chromones/chemistry , Chromones/therapeutic use , Humans , Melanoma/drug therapy , Quinazolines/chemical synthesis , Quinazolines/therapeutic use , Structure-Activity RelationshipABSTRACT
Live imaging is a powerful technique that can be used to characterize the fate and location of stem cells in animal models. Here we investigated the characteristics and in vitro cytotoxicity of human mesenchymal stem cells (MSCs) labeled with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, MNPs@SiO2(RITC). We also conducted various in vivo-uptake tests with nanoparticle-labeled human MSCs. MNPs@SiO2(RITC) showed photostability against ultraviolet light exposure and were nontoxic to human MSCs, based on the MTT, apoptosis, and cell cycle arrest assays. In addition, MNPs@SiO2(RITC) did not affect the surface phenotype or morphology of human MSCs. We also demonstrated that MNPs@SiO2(RITC) have stable retention properties in MSCs in vitro. Furthermore, using optical and magnetic resonance imaging, we successfully detected a visible signal from labeled human MSCs that were transplanted into NOD.CB17-Prkdc(SCID) (NOD-SCID) mice. These results demonstrate that MNPs@SiO2(RITC) are biocompatible and useful tools for human MSC labeling and bioimaging. FROM THE CLINICAL EDITOR: The characteristics and in vitro cytotoxicity of human mesenchymal stem cells (MSCs) labeled with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, RITC were investigated in this study. RITC showed photostability against ultraviolet light exposure and was nontoxic to human MSCs. Using both optical and magnetic resonance imaging, successful detection of signal from labeled human MSCs transplanted into mice is demonstrated.
Subject(s)
Drug Carriers/chemistry , Fetal Blood/cytology , Magnetic Resonance Imaging/methods , Mesenchymal Stem Cells/cytology , Nanoparticles/adverse effects , Rhodamines , Silicon Dioxide/chemistry , Apoptosis/drug effects , Cell Survival/drug effects , Cells, Cultured , Contrast Media/chemistry , Drug Carriers/adverse effects , Fetal Blood/drug effects , Humans , Image Enhancement/methods , Magnetics , Mesenchymal Stem Cells/drug effects , Rhodamines/adverse effects , Staining and Labeling/methodsABSTRACT
Natural cytotoxicity receptors (NCRs) are major activating receptors involved in NK cytotoxicity. NCR expression varies with the activation state of NK cells, and the expression level correlates with NK cells' natural cytotoxicity. In this study, we found that Gö6983, a PKC inhibitor, induced a remarkable increase of NCR expression on primary NK cells, but other PKC inhibitors and NK cell stimulators such as IL-2 and PMA, did not. Gö6983 increased the expression of NCR in a time- and concentration-dependent manner. Furthermore, Gö6983 strongly upregulated the surface expression of death ligands FasL and TRAIL, but not cytotoxic molecules perforin and granzyme B. Unlike two other NK stimulating molecules, IL-2, and PMA, Gö6983 did not induce NK cell proliferation. Up-regulation of NCRs and death ligands on NK cells by Gö6983 resulted in a significant enhancement of NK cytotoxicity against various cancer cell lines. Most importantly, administration of Gö6983 effectively inhibited pulmonary tumor metastasis in mice in a dose-dependent manner. These results suggest that Gö6983 functions as an NK cell activating molecule (NKAM); this NKAM is a novel anti-cancer and anti-metastasis drug candidate because it enhances NK cytotoxicity against cancer cells in vivo as well as in vitro.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/prevention & control , Indoles/pharmacology , Killer Cells, Natural/immunology , Liver Neoplasms/prevention & control , Lung Neoplasms/prevention & control , Maleimides/pharmacology , Animals , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/secondary , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Fas Ligand Protein/metabolism , Female , Flow Cytometry , Humans , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Lung Neoplasms/immunology , Lung Neoplasms/secondary , Mice , Mice, Inbred C57BL , Natural Cytotoxicity Triggering Receptor 1/genetics , Natural Cytotoxicity Triggering Receptor 1/metabolism , Natural Cytotoxicity Triggering Receptor 2/genetics , Natural Cytotoxicity Triggering Receptor 2/metabolism , Natural Cytotoxicity Triggering Receptor 3/genetics , Natural Cytotoxicity Triggering Receptor 3/metabolism , Protein Kinase C/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Cells, CulturedABSTRACT
Exposure to methylmercury causes severe damage to various tissues and organs in humans. Although a variety of fluorescent chemosensors have been exploited, only few biological monitoring systems for organomercury species have been described to date. In this report, we describe an irreversible rhodamine chemosensor for the detection of methylmercury and real-time monitoring of methylmercury in living cells and organisms.
Subject(s)
Hydrazines/chemistry , Methylmercury Compounds/analysis , Rhodamines/chemistry , Spectrometry, Fluorescence/methods , Sulfur/chemistry , Animals , Cell Survival , HeLa Cells , Humans , Semicarbazides/chemical synthesis , Titrimetry , Zebrafish/metabolismABSTRACT
Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Abeta42 fibrils using [(125)I]TZDM. All the isoindolone derivatives showed very good binding affinities with K(i) values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (K(i)=0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (K(i)=0.52 nM) and PIB (K(i)=0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Abeta fibrils.
Subject(s)
Amyloid beta-Peptides/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Isoindoles/chemistry , Isoindoles/pharmacology , Amyloid beta-Peptides/metabolism , Aniline Compounds , Benzothiazoles/chemistry , Indoprofen/chemistry , Molecular Structure , Protein Binding , Structure-Activity Relationship , ThiazolesABSTRACT
Though many studies have been published about therapeutic potentials of selective 5-HT7R ligands, there have been few biased ligands of 5-HT7R. The development of potent and selective biased ligands of 5-HT7R would be of great help in understanding the relationship between pharmacological effects and G protein/ß-arrestin signaling pathways of 5-HT7R. In order to identify 5-HT7R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and ß-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4- d]azepine 1g was discovered as the ß-arrestin biased ligand of 5-HT7R. In an electroencephalogram (EEG) test, 1g increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time.
Subject(s)
Azepines/chemistry , Receptors, Serotonin/metabolism , Sleep/drug effects , beta-Arrestins/metabolism , Animals , Drug Stability , Eye Movements/drug effects , HEK293 Cells , Humans , Ligands , Male , Mice, Inbred C57BL , Mice, Inbred ICR , Molecular Docking Simulation , Phenols/pharmacology , Serotonin Antagonists/pharmacology , Signal Transduction/drug effects , Sleep, REM/drug effects , Structure-Activity Relationship , Sulfonamides/pharmacology , beta-Arrestins/agonistsABSTRACT
In this study, we designed a library of compounds based on the structures of well-known ligands of the 18 kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aß-induced toxicity in vitro and in vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent in vitro and in vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD.
Subject(s)
Alzheimer Disease/drug therapy , Benzimidazoles/chemistry , Benzimidazoles/therapeutic use , Mitochondria/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Cognition/drug effects , Humans , Ligands , Male , Membrane Potential, Mitochondrial/drug effects , Memory/drug effects , Mice, Transgenic , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Models, Molecular , Rats, Sprague-Dawley , Receptors, GABA/metabolismABSTRACT
A new, selective chemosensor has been developed to detect cyanide in water at micromolar concentrations. The acridinium salt used in this sensor system is prepared in a single step from an acridine orange base. Detection is based on the irreversible, 1:1 stoichiometric, nucleophilic addition of cyanide to the 9-position of the acridinium ion. This process induces a large decrease in fluorescence intensity and a marked color change. The selectivity of the system in aqueous media for CN- over other anions is remarkably high. Also, the sensitivity of both the fluorescence- and colorimetric-based assay is below the 1.9 microM suggested by the World Health Organization (WHO) as the maximum allowable cyanide concentration in drinking water. Thus, the chemodosimeter should be applicable as a practical system for the monitoring of CN- concentrations in aqueous samples. [structure: see text]
Subject(s)
Acridines/chemistry , Cyanides/analysis , Fluorescent Dyes/chemistry , Water Supply/analysis , Acridine Orange , Colorimetry , Dimethyl Sulfoxide , SolventsABSTRACT
To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Acylation , Animals , Antidepressive Agents/pharmacokinetics , CHO Cells , Carbazoles/pharmacokinetics , Cricetulus , HEK293 Cells , Humans , Male , Mice , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
5-HT7 receptor (5-HT7R) agonists and antagonists have been reported to be used for treatment of neuropathic pain and depression, respectively. In this study, as a novel scaffold for 5-HT7R modulators, we designed and prepared a series of biphenyl-3-yl-methanamine derivatives with various amino groups. Evaluation of functional activities as well as binding affinities of the title compounds identified partial agonists (EC50 = 0.55-3.2 µM) and full antagonists (IC50 = 5.57-23.1 µM) depending on the amino substituents. Molecular docking study suggested that the ligand-based switch in functional activity from agonist to antagonist results from the size of the amino groups and thereby different binding modes to 5-HT7R. In particular, interaction of the ligand with Arg367 of 5-HT7R is shown to differentiate agonists and antagonists. In the pharmacophore model study, two distinct pharmacophore models can tell whether a ligand is an agonist or an antagonist. Taken together, this study provides valuable information for designing novel compounds with selective agonistic or antagonistic properties against 5-HT7R.
Subject(s)
Drug Design , Molecular Docking Simulation , Receptors, Serotonin/metabolism , Amines/chemistry , Biphenyl Compounds/chemistry , Humans , Ligands , Protein Binding , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
Design and synthesis of a new series of 5,6-diarylimidazo[2,1-b]thiazole derivatives possessing terminal aryl sulfonamide moiety are described. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 8a, 8b, 8n, 8q, 8t, and 8u showed the highest mean % inhibition values over the 57 cell line panel at 10 µM, and they were further tested in 5-dose testing mode to determine their IC50 values. Among the six compounds, compound 8u possessing terminal para-hydroxybenzenesulfonamido moiety and ethylene linker showed the highest potency. It demonstrated superior potency than Sorafenib against eight different cell lines, and was equipotent to Sorafenib against COLO 205 colon cancer cell line. Its IC50 values over NCI-H460 non-small cell lung cancer cell line and MCF7 breast cancer cell line were 0.845 µM and 0.476 µM, respectively. Compounds 8a, 8b, 8q, 8t, and 8u showed high selectivity indices towards cancer cells over L132 normal lung cell line. Compound 8u showed potential inhibitory effects over the components of ERK pathway. Its IC50 value over V600E-B-RAF and C-RAF kinases were 39.9 nM and 19.0 nM, respectively.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Thiazoles/chemistryABSTRACT
Ring-closing metathesis reactions of para-disubstituted aromatic substrates produced macrocyclic [n.n]-, and [n.n.n]paracyclophanes efficiently through dimerization and trimerization reactions. Sufficiently long alkyl chains allowed direct monocyclizations to yield [n]paracyclophanes. A small library of paracyclophanes were generated by the combinatorial cross-metathesis approach.
ABSTRACT
The stereoselectivity of the spontaneous intramolecular cyclization of 2-(benzenesulfonyl)-2-(4-((trimethylsilyl)methyl)-4-pentenyl)tetrahydropyrans substituted by alkyl groups at various ring positions has been examined. For the 4- and 6-methyl derivatives, formation of the spirocyclic center occurs exclusively anti to the methyl. The outcome in the 5-methyl example is a 3.7:1 syn/anti split. For the trans-4,6-dimethyl derivative, the substituents act in a reinforcing manner and direct cyclization uniquely in one direction. Both the cis and trans bicyclic ethers ring close on that pi-surface of the intermediate oxonium ion syn to the angular hydrogen. The results are rationalized in terms of the predilection of the associated oxonium ions for nucleophilic capture via a chairlike or twist-boat transition state.