Hiroki Shimizu

Solid phase synthesis of polylactosamine oligosaccharide

Abstract Solid phase synthesis of polylactosamine oligosaccharide was performed starting from resin supported lactose 1a,b . Glycosylation of 1a with the lactosamine unit 6 followed by delevulinoylation afforded tetrasaccharides, which were further converted into hexa- and octasaccharide and was cleaved from resin by TrBF 4 in CH 2 Cl 2 to afford 7 . Ester linked 1b was converted in a similar manner into hexasaccharide that was liberated under basic conditions to give 8 . Subsequent deprotection into 9 was performed in three steps.

Lead optimization of novel p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold.

With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a.

Discovery of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors. Part 1: Hit-to-lead study and structure-activity relationship

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure-activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKbeta was constructed.

A Precision Angle Sensor Using a Multi-cell Photodiode Array

Abstract This paper describes a compact and precision angle sensor based on laser autocollimation. Instead of using a conventional bi-cell photodiode (PD) as the detector, a new PD array with 16 cells is specifically designed and fabricated with lithography facilities available at the university. The width of each cell is designed to be 40 μm, which is slightly smaller than the light spot size on the focal plane of the objective lens. Experimental results have shown that the sensor has a resolution of 0.01 arc-seconds and a measurement range of 2300 arc-seconds, which is approximately 15 times larger than the range of the same sensor with a bi-cell PD.

Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 3: Exploration of effective compounds in arthritis models

We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.

Development of Highly Potent D-Glucosamine-Based Chiral Fluorescent Labeling Reagents and a Microwave-Assisted β-Selective Glycosidation of a Methyl Glycoside Reagent

We synthesized new chiral fluorescence labeling reagents having a 2,3-anthracenedicarboximide group from D-glucosamine, and it was possible to introduce target alcohols at the anomeric positions of the reagents with β-selectivity by glycosidations. Especially, it was possible to use methyl glycoside reagent as a glycosyl donor with a Lewis acid and microwave irradiation, and it gave selectively β-glycoside while the reaction without microwave irradiation gave α- and β-mixed glycosides. Those reagents showed very high chiral discrimination ability, and they made it possible to separate the eight stereoisomers of 4,8,12,16-tetramethylheptadecanol by HPLC after derivatizations.

Fundamental study on the new probe technique for the nano-CMM based on the laser trapping and Mirau interferometer

The nano-CMM as a coordinate measuring machine for micron-sized 3-D shapes is required to satisfy the measuring range of about a cubic centimetre and the accuracy of less than 50 nm. In order to develop such a nano-CMM, the probe with a microsphere must achieve detecting accuracy of nanometre order and a contact pressure force of less than 10−5 N. In this paper, a new probe technique for nano-CMM using a laser trapped microsphere is proposed. The principle of measurement based on the laser trapping technique and the microscope interferometer is presented. Computer simulations of radiation pressure force are performed to develop the laser trapping probe experimental system. Three-dimensional trapping of a microsphere is achieved. The contact position is estimated by measuring the displacement of the microsphere.

Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: improvement of potency in vitro and in vivo.

We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds showed inhibitory activity of TNFα production in mice.

Synthesis of (3R,4S)-3,4,5-Trihydroxy-4-methylpentylphosphonic Acid as a Potential Inhibitor of the Nonmevalonate Pathway

The nonmevalonate pathway is widely found in higher plants and in many eubacteria, including pathogenic ones, but not in mammals. Identifying a nonmevalonate pathway inhibitor would greatly contribute to the search for new herbicides and antibacterial drugs to treat, for example, malaria. We describe here the synthesis of (3R,4S)-3,4,5-trihydroxy-4-methylpentylphosphonic acid as a candidate for inhibiting MEP cytidylyltransferase, which is the third step on the nonmevalonate pathway.

Optical radiation pressure micromachining using a small particle

This paper presents a new micro-machining using optical radiation pressure induced by incident laser light, which is based on laser trapping technology. In order to verify the feasibility of our proposed new micro-machining, we construct the experimental system and carry out the fundamental experiments. As a result, we found that the proposed micro-machining will make it possible to remove effectively the surface up to the depth of several nm using the particles trapped by the optical radiation pressure, even if the pressure force is as small as 0.1nN.