[show abstract][hide abstract] ABSTRACT: Fluorescent boronic acids are very useful for the design and synthesis of carbohydrate sensors. In an earlier communication, we first described the effort of developing water soluble fluorescent alpha-amidoboronic acids, which change fluorescence upon sugar binding. In this report, we describe a general method of functionalizing such boronic acids and their applications in the preparation of bis-alpha-amidoboronic acids with significantly enhanced binding for oligosaccharides as compared to their monoboronic acid counterparts. The advantages of good water solubility, easy modification to generate diversity, and modularity in synthesis will make alpha-amidoboronic acids very useful building blocks for future synthesis of boronic acid-based fluorescent sensors.
[show abstract][hide abstract] ABSTRACT: Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC(50)=0.58+/-0.10 microM), 7d (IC(50)=1.00+/-0.16 microM), 8l (IC(50)=1.06+/-0.14 microM), 7i (IC(50)=1.17+/-0.19 microM) and 7a (IC(50)=1.29+/-0.15 microM) possessed better HDACs inhibitory activity than Vorinostat (IC(50)=1.48+/-0.20 microM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure-activity relationships are also briefly discussed.
[show abstract][hide abstract] ABSTRACT: A novel class of L-lysine derivatives as aminopeptidase N (APN) inhibitors was designed and synthesized. Activity evaluation showed that compound C7 (IC(50) = 9.6 +/-1.3 microM) and C20 (IC(50) = 13.6 +/- 1.9 microM) were equivalent to the positive control Bestatin (IC(50) = 11.3 +/- 1.6 microM).
Protein and Peptide Letters 02/2010; 17(7):847-53. · 1.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fluoride has been found to protect boronic acids from copper(i)-mediated decomposition; such findings should be very useful for the preparation of boronic acid-based carbohydrate sensors and boronic acid conjugates using the copper(i)-mediated click reaction.
Chemical Communications 10/2009; · 6.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Chemical Biology & Drug Design 08/2009; 74(1):51-6. · 2.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Herein we report a series of novel chloramphenicol amine derivatives as aminopeptidase N (APN)/CD13 inhibitors. All compounds were synthesized starting from commercially available (1S,2S)-2-amino-1-(4-nitrophenyl) propane-1,3-diol. The preliminary biological screening showed that some compounds exhibited potent inhibitory activity against APN. It should be noted that one compound, 13b (IC(50)=7.1 microM), possess similar APN inhibitory activity compared with Bestatin (IC(50)=3.0 microM).
[show abstract][hide abstract] ABSTRACT: 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.
Biochemical and Biophysical Research Communications 05/2009; 382(1):153-6. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aminopeptidase N (APN), belonged to metalloproteinase, is an essential peptidase involved in the process of tumor invasion and metastasis. A series of tripeptide analogs with the scaffold 3-phenylpropane-1,2-diamine were designed, synthesized and evaluated for their ability to inhibit APN. Preliminary activity evaluation showed that most of target compounds possessed potent inhibitory activities against APN. With in this series, compound A6 and B6 exhibited good potency with the IC(50) values of 8.8+/-1.3 microM and 8.6+/-1.1 microM, respectively.
[show abstract][hide abstract] ABSTRACT: Carbohydrates are known to mediate a large number of biological and pathological events. Small and macromolecules capable of carbohydrate recognition have great potentials as research tools, diagnostics, vectors for targeted delivery of therapeutic and imaging agents, and therapeutic agents. However, this potential is far from being realized. One key issue is the difficulty in the development of "binders" capable of specific recognition of carbohydrates of biological relevance. This review discusses systematically the general approaches that are available in developing carbohydrate sensors and "binders/receptors," and their applications. The focus is on discoveries during the last 5 years.
Medicinal Research Reviews 04/2009; 30(2):171-257. · 9.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Escapin is an L-amino acid oxidase in the ink of a marine snail, the sea hare Aplysia californica, which oxidizes L-lysine (1) to produce a mixture of chemicals which is antipredatory and antimicrobial. The goal of our study was to determine the identity and relative abundance of the constituents of this mixture, using molecules generated enzymatically with escapin and also using products of organic syntheses. We examined this mixture under the natural range of pH values for ink-from approximately 5 at full strength to approximately 8 when fully diluted in sea water. The enzymatic reaction likely forms an equilibrium mixture containing the linear form alpha-keto-epsilon-aminocaproic acid (2), the cyclic imine Delta(1)-piperidine-2-carboxylic acid (3), the cyclic enamine Delta(2)-piperidine-2-carboxylic acid (4), possibly the linear enol 6-amino-2-hydroxy-hex-2-enoic acid (7), the alpha-dihydroxy acid 6-amino-2,2-dihydroxy-hexanoic acid (8), and the cyclic aminol 2-hydroxy-piperidine-2-carboxylic acid (9). Using NMR and mass spectroscopy, we show that 3 is the major component of this enzymatic product at any pH, but at more basic conditions, the equilibrium shifts to produce relatively more 4, and at acidic conditions, the equilibrium shifts to produce relatively more 2, 7, and/or 9. Studies of escapin's enzyme kinetics demonstrate that because of the high concentrations of escapin and L-lysine in the ink secretion, millimolar concentrations of 3, H(2)O(2), and ammonia are produced, and also lower concentrations of 2, 4, 7, and 9 as a result. We also show that reactions of this mixture with H(2)O(2) produce delta-aminovaleric acid (5) and delta-valerolactam (6), with 6 being the dominant component under the naturally acidic conditions of ink. Thus, the product of escapin's action on L-lysine contains an equilibrium mixture that is more complex than previously known for any L-amino acid oxidase.
[show abstract][hide abstract] ABSTRACT: Aminopeptidase N (APN) is an essential peptidase involved in the process of tumor invasion and metastasis. Here we describe a novel class of inhibitor with 3-phenylpropane-1,2-diamine as scaffold to APN. Preliminary activity evaluation with enzyme inhibition studies showed that compound 12i exhibited potent and selective inhibitory activity towards APN with the IC(50) value 15.5+/-1.2microM.
[show abstract][hide abstract] ABSTRACT: Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC(50) values. The most potent compounds have IC(50) values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.
Journal of Medicinal Chemistry 01/2009; 51(24):7673-88. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ink of sea hares (Aplysia californica) contains escapin, an L-amino acid oxidase that metabolizes L-lysine, thereby producing a mixture that kills microbes and deters attacking predators. This secretion contains H2O2,ammonia, and an equilibrium mixture of "escapin intermediate product" (EIP-K) that includes alpha-keto-epsilon-aminocaproic acid and several other molecules. Components of the equilibrium mixture react nonenzymatically with H2O2 to form "escapin end product" (EEP-K), which contains delta-aminovaleric acid and delta-valerolactam. The proportions of the molecules in this equilibrium mixture change with pH, and this is biologically important because the secretion is pH 5 when released but becomes pH 8 when fully diluted in seawater. The goal of the current study was to identify which molecules in this equilibrium mixture are bactericidal. We show that a mixture of H2O2 and EIP-K, but not EEP-K, at low mM concentrations is synergistically responsible for most of the bactericidal activity of the secretion against Escherichia coli, Vibrio harveyi, Staphylococcus aureus,and Pseudomonas aeruginosa. Low pH enhances the bactericidal effect, and this does not result from stress associated with low pH itself. Sequential exposure to low mM concentrations of EIP-K and H2O2, in either order, does not kill E. coli. Reaction products formed when L-arginine is substituted for L-lysine have almost no bactericidal activity. Our results favor the idea that the bactericidal activity is due to unstable intermediates of the reaction of alpha-keto-epsilon-aminocaproic acid with H2O2.
Antimicrobial Agents and Chemotherapy 11/2008; 52(12):4455-62. · 4.57 Impact Factor