Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid-Derived Imidazoles as Inhibitors of Bovine Liverβ-Glucuronidase

Abstract

The gluco-, manno-, and galacto-configured imidazopyridine-5-carboxylates 5–7, respectively, were synthesized and evaluated as inhibitors of bovine liver β-glucuronidase. The gluconolactam 15 was transformed into the gluco- and manno-imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%, respectively. Oxidation and esterification of the selectively protected gluco- and manno-configured hydroxymethyl-imidazopyridines 23 and 25, respectively (both obtained from gluconolactam 15), provided the benzhydryl esters 24 and 26, respectively. Hydrogenolysis afforded the gluco-imidazopyridine-carboxylic acid 5 and the manno-isomer 6. Similarly, the hydroxymethyl-imidazopyridine 33, obtained from galactonolactam 27, was subjected to oxidation, esterification, and deprotection to afford the galacto-configured imidazopyridine-carboxylate 7 in ten steps from the galactonolactam 27 and in an overall yield of 13%. The gluco-configured imidazole 5 is the strongest known inhibitor of β-glucuronidases (Ki = 12 nM), while the manno- and galacto-configured imidazoles 6 and 7 are micromolar inhibitors of bovine β-glucuronidase. The small difference between the inhibitory strength of the imidazopyridine-carboxylic acid 5 and the tetrazolopyridine-carboxylic acid 1, and the difference between the configurational selectivity of 5–7 as compared to the unselectivity of the corresponding lactams 3 and 4 are discussed.