Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

Abstract

The known glucaro-1,5-lactam 8, its diastereoisomers 9 -11, and the tetrahydrotetrazolopyridine-5-carboxylates 12 -14 were synthesised as potential inhibitors of b-D-glucuronidases and a-L-iduronidases. The known 2,3-di-O-benzyl-4,6-O-benzylidene-D-galactose (16) was transformed into the D-galactaroand L-altraro-1,5-lactams 9 and 11 via the galactono-1,5-lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41, led to the D-glucaro-1,5-lactam 8, D-galactaro-1,5-lactam 9, L-idaro-1,5-lactam 10, and L-altraro-1,5-lactam 11 in ten steps and in an overall yield of 4 -20%. The anhydride 41 was transformed into the L-thre-A C H T U N G T R E N N U N G uronate 46. Olefination of 46 to the (E)-or (Z)-alkene 47 or 48 followed by reagent-or substrate-controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 -11. The tetrazoles 12 -14 were prepared in an overall yield of 61 -81% from the lactams 54, 28, and 67, respectively, by treatment with Tf 2 A C H T U N G T R E N N U N G O and NaN 3 , followed by saponification, esterification, and hydrogen-A C H T U N G T R E N N U N G olysis. The lactams 8 -11 and 40 and the tetrazoles 12 -14 are medium-to-strong inhibitors of b-D-glucuronidase from bovine liver. Only the L-ido-configured lactam 10 (K i = 94 mM) and the tetrazole 14Introduction. -b-D-Glucuronidases (EC 3.2.1.31, family 2) 1 ) and a-L-iduronidases (EC 3.2.1.76, family 39) remove glycuronic acid residues from the non-reducing end of glycosaminoglycans such as chondroitin sulfate and hyaluronic acid.

Probing the Interaction of the Hydroxy Group at C(4) of Lactone-Type Inhibitors withβ-Glucosidases andβ-Galactosidases

“…Conformational flexibility of glycosidase inhibitors may indeed decrease selectivity, particularly when the inhibitor possesses a substitutent which interacts strongly with the enzyme, as exemplified by monocyclic, rather flexible lactone-type inhibitors, where analogues that interact more strongly with the catalytic acid are less selective inhibitors of a-vs. b-glycosidases 5 ) [21]. Similarly, galacto-and gluco-configured glycarolactams inhibit bovine liver b-glucuronidase to about the same extent (K i % 30 nM), while the corresponding galacto-and gluco-configured imidazoles inhibit this enzyme to a very different extent (K i = 6 mM vs. 12 nM), similarly to the analogous tetrazoles (K i = 6 mM vs. 25 nM) [14] [22]. That the imidazoles and tetrazoles behave similarly is in agreement with the assumption that the selectivity differences are correlated with the flexibility rather than with the basicity of the inhibitors.…”

“…See [14]. The pK HA values were determined in H 2 O by potentiometric titration with 0.1N HCl at 258. b-Glucosidases from sweet almonds (3.2.1.21, as lyophilised powder), b-glucosidase from C. saccharolyticum (3.2.1.21, as lyophilised powder), b-galactosidase from bovine liver (3.2.1.23, as lyophilised powder), b-galactosidase from E. coli (3.2.1.23, as lyophilised powder), and all nitrophenyl glycopyranosides were purchased from Sigma and used without any further purification.…”

“…-Regioselective opening of the 1,3-dioxane ring of the benzylidene acetal 15 (prepared from D-galactose in eight steps and an overall yield of 13% [14]) with TfOH and Et 3 A C H T U N G T R E N N U N G SiH [15] gave the secondary alcohol 16 (86%; Scheme). The alcohol 16 was triflated to 17 (61%) that was purified by chromatography on silica gel.…”

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

“…The strength of the inhibition by such N-heterocycles correlates with their basic properties and with the extent of their interaction with the catalytic acid of the glycosidases [2] [10] [11]. This correlation should also be valid for the inhibition of b-glucuronidases 3 ), and imidazopyridine-5-carboxylates are expected to be stronger glycuronidase inhibitors than the corresponding known glycarolactam and tetrazolopyridine-5-carboxylates [17] [18]. This expectation is also in agreement with the obser-of this galacturonate, possessing an axial leaving group at C(4), occurred particularly readily.…”

“…The galacto-configured selectively O-benzylated imidazopyridine 33 was prepared from the partially benzylated galactono-1,5-lactam 27 [17] (Scheme 3). Acetylation of 27 to the diacetate 28 (99%), treatment with Lawesson's reagent to afford the thionolactam 29 (85%), and annulation of the imidazole ring as described for 16 provided the dihydroxyimidazopyridine 30.…”