RESUMO
In a previous study, a novel anthraquinone analog BW-AQ-101 was identified as a potent inducer of MDM2 degradation, leading to upregulation of p53 and apoptosis in cell culture studies. In animal models of acute lymphocytic leukemia, treatment with BW-AQ-101 led to complete disease remission. In this study, we systematically investigated the effect of substitution patterns of the core anthraquinone scaffold. Through cytotoxicity evaluation in two leukemia cell lines, the structure-activity relationship of thirty-two analogs has been examined. Several analogs with comparable or improved potency over BW-AQ-101 have been identified. Western-blot assays verified the effect of the potent compounds on the MDM2-p53 axis. The study also suggests new chemical space for further optimization work.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Antraquinonas/síntese química , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células K562 , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A second-generation sulfonyl azide-based fluorescent probe, 2,6-DNS-Az, has been developed for the quantitative detection of H2S in aqueous media such as phosphate buffer and bovine serum. Compare to the first-generation 1,5-DNS-Az probe, this probe shows both high sensitivity in phosphate buffer without the need for addition of surfactant and selectivity for sulfide over other anions and biomolecules, and thus can be used as a useful tool for detection of H2S in the biological system.
Assuntos
Azidas/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , FluorescênciaRESUMO
Fibrinogen is essential in the intrinsic and extrinsic blood coagulation process. Inhibition of fibrinogen aggregation could lead to anticoagulation effects. The availability of methods for easy quantitative evaluation of the coagulation process is critical to studying coagulation and its inhibition. A commonly used method is UV-Vis absorbance (405 nm) detection by a micro-plate reader. However, because of the heterogeneous nature of the resulting mixture in a coagulation process, transmission-based optical measurements give large variations. Herein, a very simple and easy method is developed for the quantitative measurements of the coagulation process. The method was validated using three known thrombin inhibitors: 4-(2-aminoethyl) benzenesulfonyl fluoride (IC50: 0.01 mM), p-amidinophenyl methanesulfonyl fluoride (IC50: 0.18 mM) and PMSF (IC50: 0.23 mM).
Assuntos
Coagulação Sanguínea , Técnicas de Laboratório Clínico/métodos , Fibrinogênio/metabolismoRESUMO
Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications.
Assuntos
Benzotiazóis/química , DNA/química , Nitrilas/química , Compostos de Sulfidrila/química , Química Click , Ciclização , DNA/síntese químicaRESUMO
A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC(50) values below 1 µM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.
Assuntos
Antimaláricos/síntese química , Curcumina/análogos & derivados , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/toxicidade , Desenho de Fármacos , Células HeLa , Humanos , Plasmodium falciparum/efeitos dos fármacos , Relação Quantitativa Estrutura-AtividadeRESUMO
In this letter, a high-throughput virtual screening was accomplished to identify potent inhibitors against AI-2 quorum sensing on the basis of Vibrio harveyi LuxPQ crystal structure. Seven compounds were found to inhibit AI-2 quorum sensing with IC(50) values in the micromolar range, and presented low cytotoxicity or no cytotoxicity in V. harveyi.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Fosfotransferases/metabolismo , Percepção de Quorum/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Vibrio/efeitos dos fármacos , Proteínas de Bactérias/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Fosfotransferases/química , Conformação Proteica , Fatores de Transcrição/química , Vibrio/crescimento & desenvolvimento , Vibrio/metabolismo , Vibrioses/tratamento farmacológicoRESUMO
The boronic acid group is widely used in chemosensor design due to its ability to reversibly bind diol-containing compounds. The thermodynamic properties of the boronic acid-diol binding process have been investigated extensively. However, there are few studies of the kinetic properties of such binding processes. In this report, stopped-flow method was used for the first time to study the kinetic properties of the binding between three model arylboronic acids, 4-, 5-, and 8-isoquinolinylboronic acids, and various sugars. With all the boronic acid-diol pairs examined, reactions were complete within seconds. The k(on) values with various sugars follow the order of D-fructose>D-tagatose>D-mannose>D-glucose. This trend tracks the thermodynamic binding affinities for these sugars and demonstrates that the 'on' rate is the key factor determining the binding constant.
Assuntos
Ácidos Borônicos/química , Hexoses/química , Água/química , Frutose/química , Glucose/química , Concentração de Íons de Hidrogênio , Isoquinolinas/química , Cinética , Manose/química , Espectrometria de Fluorescência , TermodinâmicaRESUMO
The biomedical applications of gold nanoparticle (GNP) are extraordinarily promising due to its special optical properties. However, before transforming into real clinical test, a systematic understanding of the physiological interactions of GNP becomes imperative. For example, protein-GNP interactions and their biological consequences are the most fundamental and exigent for the related studies in cell level. In this study, we report on our findings that the interaction of GNP and fibrinogen (fg) could induce blood clot, one important blood protein, under near-physiological conditions. Firstly, through different characterization methods, namely, UV spectrum, dynamic lighter scattering (DLS) and atomic force microscopy (AFM), fg-GNP clots with the microm size were found to be formed and their average size is time- and concentration dependent. Besides, the dissociation constant was calculated to be 1.36 - 2.05 microg/mL (nM level), suggesting that the interaction between fg and GNP is very strong. Finally, by scrutinizing the fg sequences, this strong binding was found to originate from many Cys residues distributed in alpha, beta, and gamma chains of fg through Au-S bond. Most of these Cys residues are in the form of disulfide bonds, which locate at the central E domain and flank parts of C-terminal and N-terminal in the coil-coil region.
Assuntos
Fibrinogênio/metabolismo , Ouro/farmacologia , Nanopartículas Metálicas/química , Nanopartículas/química , Fibrinogênio/química , Ouro/química , Humanos , Luz , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Nanotecnologia , Tamanho da Partícula , Ligação Proteica , Espalhamento de Radiação , Espectrofotometria Ultravioleta , Trombose/sangueRESUMO
The boronic acid group is an important recognition moiety for sensor design. Herein, we report a series of isoquinolinylboronic acids that have extraordinarily high affinities for diol-containing compounds at physiological pH. In addition, 5- and 8-isoquinolinylboronic acids also showed fairly high binding affinities towards D-glucose (K(a)=42 and 46 M(-1), respectively). For the first time, weak but encouraging binding of cis-cyclohexanediol was found for these boronic acids. Such binding was coupled with significant fluorescence changes. Furthermore, 4- and 6-isoquinolinylboronic acids also showed the ability to complex methyl α-D-glucopyranose (K(a)=3 and 2 M(-1), respectively).
Assuntos
Álcoois/química , Ácidos Borônicos/síntese química , Cicloexanóis/química , Corantes Fluorescentes/síntese química , Isoquinolinas/síntese química , Ácidos Borônicos/química , Técnicas de Química Combinatória , Fluorescência , Corantes Fluorescentes/química , Glucose/química , Concentração de Íons de Hidrogênio , Isoquinolinas/química , Estrutura Molecular , Solubilidade , Estereoisomerismo , Água/químicaRESUMO
Herein a water-soluble 'click' modified coumarin-based fluorescent probe for hydrogen peroxide is reported. This probe shows significant intensity increases (up to 5 fold) in near-green fluorescence upon reaction with hydrogen peroxide, and good selectivity over other reactive oxygen species.
RESUMO
Bacteria can regulate community-wide behaviors including biofilm formation, virulence, conjugation, sporulation, and swarming motility through a process called quorum sensing. Inhibitors and antagonists of bacterial quorum sensing are important research tools and potential therapeutic agents. In this review, we have summarized recent developments in this area.
Assuntos
Antibacterianos/química , Bactérias/efeitos dos fármacos , Oligopeptídeos/química , Inibidores de Proteínas Quinases/química , Percepção de Quorum/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/farmacologia , Bactérias/enzimologia , Histidina Quinase , Oligopeptídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/efeitos dos fármacos , Percepção de Quorum/fisiologia , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Quorum sensing has attracted much attention due to its involvement in pathologically relevant events such as biofilm formation, virulence factor production, and sporulation. Inhibitors of quorum sensing are important research tools and potential therapeutic agents. In this paper, we describe a phenothiazine structural scaffold as a new type of quorum sensing inhibitors with IC(50) values in the single digit micro molar range in Vibrio harveyi.
Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/farmacologia , Boratos/farmacologia , Fenotiazinas/farmacologia , Percepção de Quorum/efeitos dos fármacos , Vibrio/efeitos dos fármacos , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Antibacterianos/química , Fenotiazinas/química , Relação Estrutura-AtividadeRESUMO
Bacterial quorum sensing plays a very important role in the regulation of biofilm formation, virulence, conjugation, sporulation, and swarming mobility. Inhibitors of bacterial quorum sensing are important research tools and potential therapeutic agents. In this paper, we describe for the first time the discovery of several boronic acids as single digit micromolar inhibitors of bacterial quorum sensing in Vibrio harveyi.
Assuntos
Ácidos Borônicos/administração & dosagem , Percepção de Quorum/fisiologia , Vibrio/fisiologia , Relação Dose-Resposta a Droga , Percepção de Quorum/efeitos dos fármacos , Vibrio/efeitos dos fármacosRESUMO
Bacteria can coordinate community-wide behaviors through quorum sensing, that is, the secretion and sensing of autoinducer (AI) molecules. Bacterial quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, bacterial virulence, and drug resistance. Inhibitors of bacterial quorum sensing could therefore be useful therapeutics. Herein we report for the first time the discovery of several pyrogallol compounds as single digit micromolar inhibitors of bacterial quorum sensing in Vibrio harveyi.
Assuntos
Pirogalol/análogos & derivados , Pirogalol/farmacologia , Percepção de Quorum/efeitos dos fármacos , Vibrio/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Pirogalol/química , Vibrio/fisiologiaRESUMO
A new series of thiazolylcoumarin derivatives was synthesized. The designed strategy embraced a molecular hybridization approach which involves the combination of the thiazole and coumarin pharmacophores together. The new hybrid compounds were tested for in vitro antitumor efficacy over cervical (Hela) and kidney fibroblast (COS-7) cancer cells. Compounds 5f, 5h, 5m and 5r displayed promising efficacy toward Hela cell line. In addition, 5h and 5r were found to be the most active candidates toward COS-7 cell line. The four active analogs, 5f, 5h, 5m and 5r were screened for in vivo antitumor activity over EAC cells in mice, as well as in vitro cytotoxicity toward W138 normal cells. Results illustrated that 5r has the highest in vivo activity, and that the four analogs are less cytotoxic than 5-FU toward W138 normal cells. In this study, 3D pharmacophore analysis was performed to investigate the matching pharmacophoric features of the synthesized compounds with trichostatin A. In silico studies showed that the investigated compounds meet the optimal needs for good oral absorption with no expected toxicity hazards.
RESUMO
A new series of isatin-ß-thiocarbohydrazones was synthesized based on the pharmacophoric features of triapine required for metal chelation. Our strategy involved the modifications of triapine basic skeleton by replacing pyridinyl moiety with isatin which retains the tridentate feature of triapine needed for metal chelation. The new compounds were esteemed for their antitumor efficacy against cervical cancer (Hela) and kidney fibroblast cancer (COS-7) cell lines. Compounds 4c, 4d, 5c and 5e exhibited remarkable efficacy against Hela cell line. In addition, compounds 4c, 4k, 4e, 5c and 5e displayed an outstanding efficacy against COS-7 cell line. Compounds 4c, 4k, 4e, 5c and 5e were examined for their in vivo antitumor efficacy against Ehrlich ascites carcinoma (EAC) in mice. Pharmacophore mapping was performed to study the structural features of the synthesized compounds compared to triapine and to identify the essential moieties required for potent and selective antitumor activity.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Ehrlich/patologia , Hidrazinas/química , Indóis/síntese química , Indóis/farmacologia , Isatina/química , Micro-Ondas , Tioureia/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Células COS , Carcinoma de Ehrlich/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Masculino , Camundongos , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/farmacologiaRESUMO
A new transformation of 2-azido-1-hydroxy-containing compounds to nitriles with one carbon less than the starting materials by oxidation was reported. The reaction can be performed under mild conditions.
RESUMO
A stable and highly selective fluorescent probe has been designed and synthesized for the rapid detection of fluoride ions (F(-)) in aqueous solution and living cells. The design was based on the high reactivity of F(-) toward a silyl group.
Assuntos
Corantes Fluorescentes/química , Fluoretos/análise , Água/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Humanos , Microscopia de Fluorescência , Espectrometria de FluorescênciaRESUMO
Hypoxia inducible factors (HIFs) are transcription factors that activate expression of multiple gene products and promote tumor adaptation to a hypoxic environment. To become transcriptionally active, HIFs associate with cofactors p300 or CBP. Previously, we found that arylsulfonamides can antagonize HIF transcription in a bioassay, block the p300/HIF-1α interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, (14)C-labeled KCN1 binding, and KCN1-surface plasmon resonance measurements provide initial support for a mechanism in which KCN1 can bind to the CH1 domain of p300 and likely prevent the p300/HIF-1α assembly. Using a previously reported NMR structure of the p300/HIF-1α complex, we have identified potential binding sites in the p300-CH1 domain. A two-site binding model coupled with IC50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis.