The aim of this study is to examine the ability of the bile acid analogues obtained by chemical modification of ursodeoxycholic acid (UDCA) for TGR5 activation. Eleven UDCA analogues including 3-or 7-methylated UDCAs and amino acid conjugates were investigated as to their ability to activate TGR5 by means of the luciferase assay. It was noteworthy that 7a a-methylated UDCA, namely 3a a,7b b-dihydroxy-7a a-methyl-5b b-cholanoic acid, had a significantly high affinity for and ability to activate TGR5 as compared to UDCA. Additionally, FXR activation ability of 7a a-methylated UDCA was low relative to that of UDCA. However, other modification of UDCA, such as the introduction of methyl group at its C-3 position and oxidation or epimerization of hydroxyl group in the C-3 position, could not elicit such remarkable effect. The present findings would provide a useful strategy for the development of TGR5-selective agonist.
Diastereoselective syntheses
Diastereoselective syntheses O 0031Diastereo-and Enantioselective Synthesis of anti-1,3-Mercapto Alcohols from α,β-Unsaturated Ketones via Tandem Michael Addition-MPV Reduction. -The addition of chiral bicyclic mercapto alcohol (I) to unsaturated ketones (II) results in the formation of anti-sulfides (III) via the diastereoselective construction of two stereogenic centers. Transformation of products (III) to the target mercapto alcohols (V) is performed via reduction of the carbonyl group, and a Wagner-Meerwein rearrangement/thiol exchange reaction under acidic conditions using BF 3 ·OEt 2 /dodecanethiol. This transformation fails for substrates (IIIh) and (IIIi) containing a phenyl group adjacent to the carbonyl group. In these cases, the transformation is performed via rearrangement of O-Mom-protected sulfides (VII) to vinyl sulfides (VIII). These intermediates are converted to mercapto alcohols (X) either via reductive ozonolysis followed by hydrolysis, or via thiol exchange reaction using dodecanethiol/Bu 2 BOTf. -(OZEKI, M.; NISHIDE, K.; TERAOKA, F.; NODE*, M.; Tetrahedron: Asymmetry 15 (2004) 5, 895-907; Kyoto Pharm. Univ., Misasagi, Yamashina, Kyoto 607, Japan; Eng.) -Klein
Aeromonas sobria serine protease (ASP) is an extracellular serine protease secreted by the organism. Here, we identified the amino acid residue of ASP that contributes to substrate specificity by using both synthetic peptides and biological protein components. The results showed that the arginine residue at position 566 (Arg-566) of ASP, which is located in the extra occluding region of ASP close to an entrance of the catalytic cavity, is involved in the substrate specificity. A substitutional point mutation of the Arg-566 residue of ASP to Ala residue (ASP[R566A]) caused a decrease of the proteolytic efficiency for a certain substrate. In addition, ASP lost the ability to recognize the primary substrate by such a point mutation, and ASP[R566A] reacted to a wide range of synthetic substrates. It is likely that Arg-566 causes an interaction with the amino acid residue at position P3 of the substrate, which is the third amino acid residue upstream from the cleavage site. Another study using ORF2 protein, a chaperone protein of ASP, further suggested that Arg-566 could also play an important role in interaction with ORF2. We therefore conclude that the Arg-566 residue of ASP is likely responsible for the selection of substrates.
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