In contrast to normal boronic acids, o-hydroxymethyl phenylboronic acid (benzoboroxole) has the capability of complexing glycopyranosides efficiently in neutral water. The measurement of association constants with a panel of model hexopyranosides indicates that the preferred mode of binding is through a cis-3,4-diol, such as that found in galactopyranosides, and mass spectrometric studies support a 1:1 binding stoichiometry. The complexation of glucopyranosides is weaker, and they are bound through their 4,6-diol unit. Although several factors may explain the exceptional carbohydrate-binding behavior of this class of hemiboronic acids, the relatively high Lewis acidity of benzoboroxoles is a likely contributing factor along with subtle factors such as intramolecular hydrogen bonds with other hydroxyl groups in the resulting anionic complex. These results with hexopyranosides suggest that biologically relevant cell-surface oligosaccharides could be targeted in water using oligomeric benzoboroxole receptors.
Mini lectins: A new class of oligosaccharide receptors (see example) was designed by exploiting several modes of molecular recognition, including the unique ability of benzoboroxoles to complex hexopyranosides. The synthesis is modular, thus well suited to targeting specific oligosaccharides using combinatorial libraries.
The steroidogenic enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the synthesis of estradiol (E(2)), a hormone well-known to stimulate the growth of estrogen-sensitive tumors. To obtain compounds able to control E(2) formation, two moieties were linked with a methylene side chain: an adenosine moiety for interacting with the cofactor-binding site and an E(2) moiety for interacting with the substrate-binding site. When tested as inhibitors of type 1 17beta-HSD, the hybrid compounds inhibited the reductive activity (E(1) into E(2)) with IC(50) values ranging from 52 to 1,000 nM. The optimal side-chain length was determined to be eight methylene groups for a 16 beta-orientation. The presence of two components (E(2) and adenosine) is essential for good inhibition, since 16 beta-nonyl-E(2) and 5-nonanoyl-O-adenosine, two compounds having only one of the components, did not inhibit the enzyme. Moreover, the 3D-structure analysis of EM-1,745 complexed with type 1 17beta-HSD showed key interactions with both substrate- and cofactor-binding sites.
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