Upregulation of p53 through induction of MDM2 degradation: Anthraquinone analogs.

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.

Microwave-assisted synthesis and antitumor evaluation of a new series of thiazolylcoumarin derivatives.

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.

Isatin-ß-thiocarbohydrazones: Microwave-assisted synthesis, antitumor activity and structure-activity relationship.

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.

A fast and simple approach to the quantitative evaluation of fibrinogen coagulation.

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).

2,6-dansyl azide as a fluorescent probe for hydrogen sulfide.

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.

Rapid and specific post-synthesis modification of DNA through a biocompatible condensation of 1,2-aminothiols with 2-cyanobenzothiazole.

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.

A fluorescent probe for rapid aqueous fluoride detection and cell imaging.

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.

Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin.

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.

Novel AI-2 quorum sensing inhibitors in Vibrio harveyi identified through structure-based virtual screening.

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.

Probing the general time scale question of boronic acid binding with sugars in aqueous solution at physiological pH.

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.

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor.

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.

Fibrinogen clot induced by gold-nanoparticle in vitro.

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.

A new class of fluorescent boronic acids that have extraordinarily high affinities for diols in aqueous solution at physiological pH.

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).

A Fluorescent Hydrogen Peroxide Probe Based on a 'Click' Modified Coumarin Fluorophore.

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.

Carbohydrate biomarkers for future disease detection and treatment.

Carbohydrates are considered as one of the most important classes of biomarkers for cell types, disease states, protein functions, and developmental states. Carbohydrate "binders" that can specifically recognize a carbohydrate biomarker can be used for developing novel types of site specific delivery methods and imaging agents. In this review, we present selected examples of important carbohydrate biomarkers and how they can be targeted for the development of therapeutic and diagnostic agents. Examples are arranged based on disease categories including (1) infectious diseases, (2) cancer, (3) inflammation and immune responses, (4) signal transduction, (5) stem cell transformation, (6) embryo development, and (7) cardiovascular diseases, though some issues cross therapeutic boundaries.

Inhibition of quorum sensing in Vibrio harveyi by boronic acids.

Bacterial quorum sensing refers to the ability of bacteria to control gene expression through the detection of a threshold concentration of certain chemicals called autoinducer(s), which are secreted by self and/or other bacteria. Quorum sensing is implicated in the regulation of pathologically relevant events such as biofilm formation, virulence, conjugation, sporulation, and swarming mobility. Inhibitors of bacterial quorum sensing are valuable research tools and potential antimicrobial agents. In this paper, we describe the discovery of several boronic acid inhibitors of bacterial quorum sensing in Vibrio harveyi with IC(50) values in the low to sub-micromolar range in whole cell assays.

Synthesis and evaluation of new antagonists of bacterial quorum sensing in Vibrio harveyi.

Bacterial quorum sensing has received much attention in recent years because of its relevance to pathological events such as biofilm formation. Based on the structures of two lead inhibitors (IC50: 35-55 microM) against autoinducer-2-mediated quorum sensing identified through virtual screening, we synthesized 39 analogues and examined their inhibitory activities. Twelve of these new analogues showed equal or better inhibitory activities than the lead inhibitors. The best compound showed an IC50 value of approximately 6 microM in a whole-cell assay using Vibrio harveyi as the model organism. The structure-activity relationship is discussed herein.

A new phenothiazine structural scaffold as inhibitors of bacterial quorum sensing in Vibrio harveyi.

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.

Inhibitors and antagonists of bacterial quorum sensing.

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.