Tsutomu Yokomatsu

Fe3O4 nanoparticle-supported Cu(II)-β-cyclodextrin complex as a magnetically recoverable and reusable catalyst for the synthesis of symmetrical biaryls and 1,2,3-triazoles from aryl boronic acids

We report here on the preparation of an efficient, easily recoverable and reusable Fe3O4 magnetic nanoparticle-supported Cu(II)-β-cyclodextrin complex catalyst for the synthesis of symmetrical biaryls and 1,2,3-triazoles from arylboronic acids. The presented Fe3O4 magnetic nanoparticle-supported Cu(II)-β-cyclodextrin complex catalyst was characterized by TEM, XRD, VSM, TGA, and FT-IR spectrometer. By using the catalyst, we have developed an efficient protocol for the homocoupling of aryl boronic acids for the synthesis of biaryls. The catalyst is also active in the synthesis of 1,2,3-triazoles via a one-pot reaction of an arylboronic acid with sodium azide in water followed by a click cyclization reaction with an alkyne at room temperature in air without any additives. The reusability of the prepared nanocatalyst was successfully examined four times with only a very slight loss of catalytic activity.

An attempt to promote neo-vascularization by employing a newly synthesized inhibitor of protein tyrosine phosphatase

Vascular endothelial growth factor (VEGF) and its receptors play a key role in angiogenesis. VEGF receptor‐2 (VEGFR‐2) has a tyrosine kinase domain, and, once activated, induces the phosphorylation of cytoplasmic signaling proteins. The phosphorylated VEGFR‐2 may be a substrate for intracellular protein tyrosine phosphatases (PTPs) which prevent VEGF signaling. We synthesized a series of α,α‐difluoro(phenyl)methylphosphonic acids (DFPMPAs) which inhibit the action of PTP. In this study, we test their effects on VEGF‐induced angiogenesis. DFPMPA‐3, the most effective inhibitor of human PTP‐1B, promoted tube formation by human umbilical vein endothelial cells (HUVEC) on Matrigel more effectively than any other DFPMPAs. The inhibitor promoted the VEGF‐induced proliferation and migration of HUVEC by inhibiting the dephosphorylation of VEGFR‐2. Its effectiveness was proven through neo‐vascularization in mice. The present findings suggest that targeting PTP to promote therapeutic neo‐vascularization may be a potential strategy.

N-arylation of amines: C–N coupling of amines with arylboronic acids using Fe3O4 magnetic nanoparticles-supported EDTA–Cu(II) complex in water

Fe3O4 magnetic nanoparticles-supported EDTA–copper(II) complex (Fe3O4-EDTA–Cu(II)) has been prepared and characterized by TEM, SEM, XRD, VSM, TGA, and FT-IR spectrometers. The catalyst was applied for the C–N coupling of arylboronic acids with amines for the preparation of N-aryl compounds. Recovery tests confirm that the catalyst can be easily recovered and reused up to eight times without significant loss of its catalytic activity.

Efficient synthesis of 2-phenyl-3-substituted furo/thieno[2,3-b]quinoxalines via Sonogashira coupling reaction followed by iodocyclization and subsequent palladium-catalyzed cross-coupling reactions

In this paper, we report the successful synthesis of new 2-phenyl-3-substituted furo/thieno[2,3-b]quinoxaline derivatives from 2-chloro-3-methoxyquinoxaline and 2-chloro-3-(methylthio)quinoxaline by a three-step approach. The Sonogashira coupling reaction of the title compounds with terminal alkynes afforded 2-methoxy-3-(phenylethynyl)quinoxaline and 2-(methylthio)-3-(phenylethynyl)quinoxaline in good to excellent yields. The iodocyclization of the resulting compounds using ICl in CH2Cl2 afforded 3-iodo-2-phenylfuro[2,3-b]quinoxaline and 3-iodo-2-phenylthieno[2,3-b]quinoxaline. The subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodo compounds led to the formation of 2,3-disubstituded furo/thieno[2,3-b]quinoxaline in high yields. All compounds were fully characterized by FT-IR, mass, 1H NMR, and 13C NMR spectral data. The synthesized quinoxaline derivatives were also screened against the two bacterial strains Escherichia coli and Micrococcus luteus.

Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene

A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2-yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5-dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2-furamide (17) possessed the most potent inhibitory activity against Ca(2+)-induced mitochondrial swelling. The structural development, synthesis and structure-activity relationship of these compounds are described.

Highly water-dispersible magnetite nanoparticle supported-palladium–β-cyclodextrin as an efficient catalyst for Suzuki–Miyaura and Sonogashira coupling reactions

We reported here a novel highly water-dispersible and recoverable magnetite supporting a palladium–β-cyclodextrin complex as an efficient catalyst in Suzuki–Miyaura and Sonogashira carbon–carbon coupling reactions. The magnetite nanoparticle supporting catalyst was characterized by FT-IR, CHN, EDS, TGA, XRD, TEM and VSM. The prepared catalyst displayed excellent activity for a wide range of substrates in aqueous solution under mild reaction conditions. The reusability of the magnetite supporting palladium–β-cyclodextrin nanocatalyst was successfully examined five times with a slight loss of catalytic activity.

Trimeric purine nucleoside phosphorylase: Exploring postulated one-third-of-the-sites binding in the transition state

Transition-state analogue inhibitors, immucillins, were reported to bind to trimeric purine nucleoside phosphorylase (PNP) with the stoichiometry of one molecule per enzyme trimer [Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.; Schramm, V. L. Biochem. 1998, 37, 8615]. In attempts to observe and better understand the nature of this phenomenon we have conducted calorimetric titrations of the recombinant calf PNP complexed with immucillin H. However, by striking contrast to the earlier reports, we have not observed negative cooperativity and we got the stoichiometry of three immucillin molecules per enzyme trimer. Similar results were obtained from fluorimetric titrations, and for other inhibitors bearing features of the transition state. However, we observed apparent cooperativity between enzyme subunits and apparent lower stoichiometry when we used the recombinant enzyme not fully purified from hypoxanthine, which is moped from Escherichia coli cells. Results presented here prove that one-third-of-the-sites binding does not occur for trimeric PNP, and give the highly probable explanation why previous experiments were interpreted in terms of this phenomenon.

Overexpressed proteins may act as mops removing their ligands from the host cells: A case study of calf PNP

Calf purine nucleoside phosphorylase (PNP) was overexpressed in Escherichia coli. The basic kinetic parameters of recombinant PNP were found to be similar to the values published previously for non-recombinant PNP from calf spleen. However, upon titration of the recombinant enzyme with the tight-binding multisubstrate analogue inhibitor DFPP-DG, endothermic as well as exothermic signals were obtained. This was not the case for PNP isolated from calf spleen for which only the endothermic process was observed. Further calorimetric titrations of the recombinant and non-recombinant enzyme with its potent and moderate ligands, and studied involving partial inactivation of the enzyme, lead to the conclusion that a part of the recombinant enzyme forms a complex with its product, hypoxanthine, although hypoxanthine was not present at any purification stage except for its natural occurrence in E. coli cells. Binding of hypoxanthine is accompanied with a large negative change of the free enthalpy, and therefore the replacement of this compound by DFPP-DG yields positive heat signal. Our data obtained with calf PNP indicate that similar processes--moping of ligands from the host cells--may take place in the case of other proteins with high overexpression yield.

A simple and novel method for the direct conversion of carboxylic acids into thioamides

We report here a simple, efficient, practical and direct method for the conversion of carboxylic acids into thioamides. As described below, the reaction of a variety of aromatic and aliphatic carboxylic acids in the presence of ammonium phosphorodithioates proceeded effectively to afford the corresponding thioamides in good yields. This thioamidation reaction is operationally straightforward and provides primary, secondary and tertiary thioamides from corresponding carboxylic acids.

Thermodynamic studies of interactions of calf spleen PNP with acyclic phosphonate inhibitors

The Gibbs binding energy and entropy/enthalpy contributions to the interaction of calf spleen purine nucleoside phosphorylase (PNP) with the novel multisubstrate analogue DFPP-DG, as well as with DFPP-G and (S)-PMP-DAP were determined by fluorescence and calorimetric studies. Results were compared with findings for guanine - a natural reaction product and inhibitor.