9,10-Phenanthrenequinone and acenaphthenequinone are shown to act as simple redox-dependent receptors toward aromatic ureas in CH(2)Cl(2) and DMF. Reduction of the o-quinones to their radical anions greatly increases the strength of hydrogen bonding between the quinone carbonyl oxygens and the urea N-hydrogens. This is detected by large positive shifts in the redox potential of the quinones with no change in electrochemical reversibility upon addition of urea guests. Cyclic voltammetric studies with a variety of possible guests show that the effect is quite selective. Only guests with two strong hydrogen donors, such as O-H bonds or amide N-H bonds, that are capable of simultaneously interacting with both carbonyl oxygens give large shifts in the redox potential of the quinones. The electronic character and conformational preference of the guest are also shown to significantly affect the magnitude of the observed potential shift. In the presence of strong proton donors the electrochemistry of the quinone becomes irreversible indicating that proton transfer has taken place. Experiments with compounds of different acidity show that the pK(a) of the protonated quinone radical is about 15 on the DMSO scale, >4 pK(a) units smaller than that of 1,3-diphenylurea. This is further proof that hydrogen bonding and not proton transfer is responsible for the large potential shifts observed with this and similar guests.

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Utilizing structure-based design, we have previously demonstrated that it is possible to obtain selective inhibitors of protein-tyrosine phosphatase 1B (PTP1B). A basic nitrogen was introduced into a general PTP inhibitor to form a salt bridge to Asp48 in PTP1B and simultaneously cause repulsion in PTPs containing an asparagine in the equivalent position [Iversen, L. F., et al. (2000) J. Biol. Chem. 275, 10300-10307]. Further, we have recently demonstrated that Gly259 in PTP1B forms the bottom of a gateway that allows easy access to the active site for a broad range of substrates, while bulky residues in the same position in other PTPs cause steric hindrance and reduced substrate recognition capacity [Peters, G. H., et al. (2000) J. Biol. Chem. 275, 18201-18209]. The current study was undertaken to investigate the feasibility of structure-based design, utilizing these differences in accessibility to the active site among various PTPs. We show that a general, low-molecular weight PTP inhibitor can be developed into a highly selective inhibitor for PTP1B and TC-PTP by introducing a substituent, which is designed to address the region around residues 258 and 259. Detailed enzyme kinetic analysis with a set of wild-type and mutant PTPs, X-ray protein crystallography, and molecular modeling studies confirmed that selectivity for PTP1B and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs.

The study of phenanthrenequinone(PQ)-modified electrodes, prepared by electropolymerization of a phenanthrenequinone-pyrrole derivative, is described. The surface-confined PQ is shown to behave similarly to PQ in solution, acting as a redox-dependent receptor toward aromatic ureas in aprotic solvents. Large, positive shifts in the E1/2 of the PQ0/- redox couple are observed in the presence of these ureas, due to a strong hydrogen bonding interaction between the PQ radical anion and urea. The effect is fully reversible. Of the substrates examined, only aromatic ureas produce a significant shift. Nonaromatic ureas or other HN and HO containing compounds have little effect on the E1/2. The magnitude of the shift is also independent of electrode coverage, allowing reproducible measurements to be made despite significant loss in material from the surface.

Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

Oxidation of a dimethylaminophenyl-substituted urea leads to a > 2000-fold increase in binding strength between the urea and a diamide guest in 0.1 M NBu4B(C6F5)4/CH2Cl2. The strength of this interaction is obscured when NBu4ClO4 or NBu4PF6 is used as the electrolyte due to competition between the neutral guest and the electrolyte anion for H-bonding to the urea cation.

Mn 1.56 Co 0.96 Ni 0.48 O 4 films with spinel structure were prepared on Al2O3 substrate by chemical solution deposition method. The microstructure of the films was studied by atomic force microscope and field-emission scanning electron microscope. The current-voltage characteristics showed Ohmic conductivity in the temperature range of 245–295K. The conduction was described by a variable range hopping model for a parabolic density of states. The advantages of high characteristic temperature, as well as high transition temperature (201K) between ferromagnetic and paramagnetic phases make the Mn1.56Co0.96Ni0.48O4 films very promising for infrared detection, especially for functional devices by integrating magnetic and electronic properties of the materials.

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