Takeo Harada

One-pot sequential glycosylation: A new method for the synthesis of oligosaccharides

Abstract Sequential one-pot glycosylations among various glycosidic donors (glycosyl bromide, glycosyl trichloroimidate, glycosyl fluoride), a β-thiophenyl glycoside derivative and a α-methyl glycoside derivative have been attempted to give the corresponding trisaccharides.

The synthesis of β-strand mimetic templates via regioselective 1,3-dipolar cycloaddition with vinylsulfone

Abstract We have developed a practical synthetic route to constrained β-strand mimetic templates by regioselective 1,3-dipolar cycloaddition of azomethine imines with vinyl sulfone. A small library of β-strand mimetic templates was generated which include potent and selective inhibitors of serine proteases.

Discovery and structure--activity relationship studies of a novel and specific peptide motif, Pro-X-X-X-Asp-X, as a platelet fibrinogen receptor antagonist.

A novel hexapeptide, H-Pro-Ser-Nva-Gly-Asp-Trp-OH 6, a specific antagonist of platelet fibrinogen receptor (GpIIb/IIIa), was discovered in a structure-activity relationship (SAR) study where the role of the N-terminal Pro moiety of an RGD-containing peptide, H-Pro-Ser-Arg-Gly-Asp-Trp-OH 1, which is a potent but not specific antagonist toward GpIIb/IIIa integrin, was investigated. This novel peptide 6 exhibits very high activity as a human platelet aggregation inhibitor (IC50 0.59 microM, human PRP/collagen) as well as marked specificity for GpIIb/IIIa. A series of substitutions at the third position (Nva residue) in this hexapeptide, focused on the conformational rigidity, led to compounds which are superior to the original novel peptide 6 with regard to anti-platelet activity. The peptides, H-Pro-Ser-Hyp-Gly-Asp-Trp-OH 17 and H-Pro-Ser-delta Pro-Gly-Asp-Trp-OH 18 with the 5-membered ring structure, which restricted the conformation of the peptide backbone at the third position, inhibited the aggregation of human platelets at submicromolar concentrations (IC50 0.39 and 0.30 microM, respectively). Further structure-activity relationship studies at each position of the peptide sequence suggest a novel motif sequence, Pro-X1-X2-X3-Asp-X4, for specific GpIIb/IIIa integrin recognition, in which the N-terminal free Pro residue and the Asp residue at the fifth position are essential to the activity. This motif sequence is summarized as follows: (1) a small amino acid such as Ser, Ala or Gly is preferable at X1 position; (2) X2 may be any amino acid, preferably a bulky amino acid such as Tle or a cyclic amino acid such as Pro; (3) X3 must be a small amino acid such as Gly; and (4) X4 is preferably an amino acid with an aromatic side chain.

Virtual screening leads to the discovery of an effective antagonist of lymphocyte function-associated antigen-1.

The binding of lymphocyte function‐associated antigen‐1 (LFA‐1) to its ligand on endothelial cells, intercellular adhesion molecule‐1 (ICAM‐1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T‐cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA‐1/ICAM‐1 interaction using ligand‐based virtual screening (VS), analogue design, and structure–activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of ∼2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA‐1 and ICAM‐1.

Synthetic approach to identification of periplaneta sex pheromones

Abstract Syntheses of the proposed structure of periplanone J ( 1 ) and its epimer 2 , and the discussion on the true structure of PJ based on the spectral study of 1,2 and the natural PJ are described.

Conformational Analysis of a Branched Sugar in Aqueous Solution Based on Molecular Mechanics and 1H-NMR Studies

Abstract MM2 and AMBER force fields in both vacuum and GB/SA solvation model were examined to find the most effective method for elucidating the conformational properties of the trisaccharide 2, which is essential to the elicitor activity of hexa-β-D-glucopyranosyl-D-glucitol ( 1 ). The NMR studies reveal that the combination of AMBER force field and GB/SA solvation treatment is quite effective in analyzing the conformation of oliosaccharide in water.

Synthesis and Structure Determination of Periplanone A Based On Molecular Mechanics Calculation

Abstract Reexamination of the stereoselectivity in the epoxidation of 10-membered exocyclic enone and the structure determination of periplanone A and B based on molecular mechanics calculation are described.

In vitro and in vivo properties of NSL-9511, a novel anti-platelet hexapeptide without an RGD sequence

Integrins are heterodimeric cell surface receptor molecules and are thought to be particularly important mediators of cell adhesion to extracellular matrix proteins, cell migration, cell-to-cell contact, etc. Many of them, such as platelet GpIIb/IIIa (fibrinogen receptor), vitronectin receptor and fibronectin receptor recognize the Arg-GlyAsp sequence (RGD) as a common recognition motif within their putative ligands [1,2]. Because the RGD sequence has been found in many types of proteins, there are apparent redundancies in integrin-ligand interactions. These redundancies are interesting aspects of integrin receptors and may be beneficial to cell functions. We are developing small peptides which are specific for each integrin as a tool for investigating ligand-integrin interactions and as agents for therapeutic uses. In this study, we have found a novel motif sequence which exhibited potent and highly specific GpIIb/IIIa antagonistic activity. In vivo and in vitro properties of one of these motif peptides are examined and discussed.