The C-Disaccharide α-C(1→3)-Mannopyranoside of N-Acetylgalactosamine Is an Inhibitor of Glycohydrolases and of Human α-1,3-Fucosyltransferase VI. Its Epimer α-(1→3)-Mannopyranoside of N-Acetyltalosamine Is Not

Abstract

The radical C-glycosidation of (-)-(1S,4R,5R, 6R)-6-endo-chloro-3-methylidene-5-exo-(phenylseleno)-7-ox abi cyclo[2. 2.1]heptan-2-one ((-)-4) with 2,3,4, 6-tetra-O-acetyl-alpha-D-mannopyranosyl bromide gave (+)-(1S,3R,4R, 5R,6R)-6-endo-chloro-5-exo-(phenylseleno)-3-endo-(1',3',4', 5'-tetra-O-acetyl-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-7-oxabi cyc lo[ 2.2.1]hept-2-one ((+)-5) that was converted into (+)-(1R,2S,5R, 6R)-5-acetamido-3-chloro-2-hydroxy-6-(1',3',4',5'-tetra-O-acetyl)-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)cyclohex -3-en- 1-yl acetate ((+)-10) and into (+)-(1R,2S,5R, 6S)-5-bromo-3-chloro-2-hydroxy-6-(1',3',4',5'-tetra-O-acetyl-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)cyclohex -3-en- 1-yl acetate ((+)-19). Ozonolysis of (+)-10 and further transformations provided 2-acetamido-2,3-dideoxy-3-C-(2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-D-galac tos e (alpha-C(1-->3)-D-mannopyranoside of N-acetylgalactosamine (alpha-D-Manp-(1-->3)CH(2)-D-GalNAc): 1). Displacement of the bromide (+)-19 with NaN(3) in DMF provided the corresponding azide ((-)-20) following a S(N)2 mechanism. Ozonolysis of (-)-20 and further transformations led to 2-acetamido-2,3-dideoxy-3-C-(2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-D-talose (alpha-C(1-->3)-D-mannopyranoside of N-acetyl D-talosamine (alpha-D-Manp-(1-->3)CH(2)-D-TalNAc): 2). The neutral C-disaccharide 1 inhibits several glycosidases (e.g., beta-galactosidase from jack bean with K(i) = 7.5 microM, alpha-L-fucosidase from human placenta with K(i) = 28 microM, beta-glucosidase from Caldocellum saccharolyticum with K(i) = 18 microM) and human alpha-1, 3-fucosyltransferase VI (Fuc-TVI) with K(i) = 120 microM whereas it 2-epimer 2 does not. Double reciprocal analysis showed that the inhibition of Fuc-TVI by 1 displays a mixed pattern with respect to both the donor sugar GDP-fucose and the acceptor LacNAc with K(i) of 123 and 128 microM, respectively.

Glycosyltransferase Inhibitors

“…The 3-OH group is probably essential for the binding of the acceptor to the active site of the enzyme. However, the (1-3)-C-disaccharide 61 was found to be a good inhibitor (K i = 120 lM) for a(1-3)fucosyltransferase VI, in relation to the affinity of the substrate (N-acetyllactosamine, K M = 32 mM) to the enzyme [119]. a-Galactosyl(1-4)-1-deoxynojirimycin (62) [120] was also found to be not a substrate but an inhibitor (IC 50 = 8 mM) for recombinant human a(1-3)fucosyltransferase [121,122].…”

The synthesis of d-C-mannopyranosides

“…Various D-Cmannopyranoside derivatives have been synthesized in order to evaluate their biological activity as lectin inhibitors relative to their O-glycoside counterpart [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. C-mannosides have also been prepared and tested as potential glycosidase and glycosyltransferase inhibitors [58][59][60][61][62][63][64], as anti-inflammatory derivatives [65], anti-tumor agents [30,66], and anti-bacterial agents [67,68].…”

Syntheses of β‐C(1→3)‐Glucopyranosides of 2‐ and 4‐Deoxy‐D‐hexoses

“…); 4.17 ± 4.11 (m, H a ÀC (6), H b ÀC(7')); 3.88 (dd, 2 J 11.7, 3 J(5,6b) 7.4, H b ÀC(6)); 3.57 (dd, 3 J(2',3') 9.4, 3 J(1',2') 2.4, HÀC(2')); 3.55 (m, HÀC(6')); 2.77 (m, HÀC (3) (1)); 76.5, 75.7 (2d, J 141, C(2'), C(6')); 74.7 (d, J 148, C(4')); 70.5 (d, J 144, C(5)); 67.8 (d, J 154, C(5')); 67.5, 64.1 (2d, J 147, J 50, C(1'), C(4)); 67.1 (d, J 153, C(3')); 63.3 (t, J 149, C(6)); 61.6 (t, J 149, C(7')); 33. (6) ( (18).…”

“…Disaccharide mimetics such as C-linked disaccharides and oligosaccharides containing them offer the advantage of being resistant to acidic and enzymatic hydrolysis [4] [5]. They are potential inhibitors of glycosidases and glycosyltransferases [6]. In this report, we apply our convergent synthetic method for the construction of C(1 3 3)-linked disaccharides [7] to the preparation of yet unknown b-C-glucopyranosides in which a hydroxymethano linker connects b-d-glucopyranose to C(3) of 2-deoxy-d-arabinohexose (see 1), 2-deoxy-d-lyxo-hexose (see 2), and 4-deoxy-d-arabino-hexose (see 3).…”