Discovery of a potent,selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.     

One-pot synthesis of 3-(2-cyanophenyl)quinazolin-4(3H)-one

Anthranilonitrile reacting with formic acid at room temperature for three days gave 64% of 3-(2-cyanophenyl)quinazolin-4(3H)-one. Under similar conditions anthranilic acid. 4-nitroaniline, and 2,5-dichloroaniline were N-formylated in good yields.Institute of Organic Chemistry and Technology, Silesian Technical University, Krzywoustego, 4, 44–100 Gliwice, Poland; e-mail: wojtex@zeus.polsl.gliwice.pl. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 922–924, July, 2000.     

Displacement affinity chromatography of protein phosphatase one (PP1) complexes

Background  

Protein phosphatase one (PP1) is a ubiquitously expressed, highly conserved protein phosphatase that dephosphorylates target protein serine and threonine residues. PP1 is localized to its site of action by interacting with targeting or regulatory proteins, a majority of which contains a primary docking site referred to as the RVXF/W motif.     

Reaction of N-Phenylbenzamidine with O-Acetylbenzeneoximoyl Chloride

The reaction of N-phenylbenzamidine with O-acetylbenzeneoximoyl chloride in methanol solution gave unexpectedly 5-methoxy-3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole, which structure was confirmed by X-ray analysis. The last step of this reaction was simulated by the PM3 semiempirical method.     

Photochemical reduction of transition metal substituted heteropoly anions in nonpolar solutions

Photochromism of [SiW11O39Ni(X)]6- as a tetraheptylammonium salt in various solvents under broadband UV light is observed in the presence of alcohols. The reaction proceeds faster with benzyl alcohol than with ethanol. Benzaldehyde is identified as the oxidized product of benzyl alcohol. Photochemistry is a reliable means to produce stable reduced transition metal substituted heteropoly tungstates in nonpolar media, where they hold promise as multielectron reduction catalysts. Preliminary reactivity toward CO2 reduction is demonstrated.     

Synthesis of purines and other fused imidazoles from acyclic amidines and guanidines

[reaction: see text] Purines, xanthines, and other fused imidazoles can be prepared from amidines or guanidines, with retrosynthetic disconnection at the ring fusion. Ring closure proceeds using Cu(I), with no special ligands required. The method allows for easy modification of the heterocyclic nucleus and is tolerant of functionality pendant to the ring system.     

Chemo- and regioselective cyclohydrocarbonylation of alpha-keto alkynes catalyzed by a zwitterionic rhodium complex and triphenyl phosphite

alpha-Keto alkynes react with CO and H(2) in the presence of catalytic quantities of the zwitterionic rhodium complex (eta(6)-C(6)H(5)BPh(3))(-)Rh(+)(1,5-COD) and triphenyl phosphite affording either the 2-, 2(3H)-, or 2(5H)-furanones in 61-93% yields. The cyclohydrocarbonylation is readily accomplished using substrates containing alkyl, aryl, vinyl, and alkoxy groups at the acetylenic terminal, as well as a variety of primary, secondary, and tertiary alkyl, aryl, and heteroaryl groups connected to the ketone functionality. Structural and electronic properties present in the starting materials mediate the chemo- and regioselectivity of the reaction.     

One-step, nonenzymatic synthesis of O-acetyl-ADP-ribose and analogues from NAD and carboxylates

O-Acetyl-ADP-ribose (OAADPR) is a metabolite produced from nicotinamide adenine dinucleotide (NAD) as a product of sirtuin-mediated protein deacetylation. We present here a simple, one-step, nonenzymatic synthesis of OAADPR from NAD and sodium acetate in acetic acid. We extended the reaction to other carboxylic acids, demonstrating that the reaction between NAD and nonaqueous carboxylate buffers produces mixtures of the corresponding 2'- and 3'-carboxylic esters.     

Albumin adsorption on unmodified and sulfonated polystyrene surfaces, in relation to cell-substratum adhesion

Albumin is commonly applied for blocking the adsorption of other proteins and to prevent the nonspecific adhesion of cells to diverse artificial substrata. Here we address the question of how effective these albumin properties are--by investigating unmodified and sulfonated polystyrene substrata with distinctly different wettabilities. As clearly shown with (125)I-radioisotopic assays, above a concentration of 10-20 μg/mL, the efficiency of bovine serum albumin (BSA) adsorption became markedly higher on the sulfonated surface than on the unmodified one. This study was assisted with the atomic force microscopy. On the unmodified surface, BSA, adsorbed from sufficiently concentrated solutions, formed a monolayer, with occasional intrusions of multilayered patches. Conversely, the arrangement of BSA on the sulfonated surface was chaotic; the height of individual molecules was lower than on the unmodified polystyrene. Importantly, the adhesion study of LNCaP and DU145 cells indicated that both surfaces, subjected to the prior BSA adsorption, did not completely loose their cell-adhesive properties. However, the level of adhesion and the pattern of F-actin organization in adhering cells have shown that cells interacted with unmodified and sulfonated surfaces differently, depending on the arrangement of adsorbed albumin. These results suggest the presence of some bare substratum area accessible for cells after the albumin adsorption to both types of investigated surfaces.