Hidetoshi Tsunoda

Synthesis of β-d-GlcpNAc-(1 → 2)-5a-carba-α-d-Manp-(1 → 6)-β-d-Glcp-O(CH2)7CH3: a reactive acceptor analog for N-acetylglucosaminyltransferase-V

Abstract The branching enzyme N-acetylglucosaminyltransferase-V (GlcNAcT-V) recognizes the trisaccharide β- d -Glc p NAc -(1 → 2)-α- d -Man p-(1 → 6)-β- d -Glc p- O(CH 2 ) 7 CH 3 (1) as its minimum substrate. We report here the chemical synthesis of β- d -Glc p NAc -(1 → 2)- 5a-carba-α- d -Man p-(1 → 6)-β- d -Glc p- O(CH 2 ) 7 CH 3 (2), a carbocyclic analog of 1 where the ring oxygen of the α- d -Man p residue is replaced by a methylene group. Trisaccharide 2 was found to be fully active as an acceptor for GlcNAcT-V, both with the enzyme isolated from hamster kidney and the one cloned from rat kidney. The kinetic parameters Km and Vmax for 1 and 2 were functionally equivalent. A preparative glycosylation reaction was performed using 2 as the acceptor with the cloned rat kidney enzyme. A tetrasaccharide formed by the addition of a GlcpNAc residue was the sole product as detected by 1H NMR spectroscopy and FAB mass spectrometry and was assigned the structure β- d -Glc p NAc -(1 → 2)-[β- d -Glc p NAc -(1 → 6)]- 5a-carba-α- d -Man p-(1 → 6)-β- d -Glc p- O(CH 2 ) 7 CH 3 (13).

Synthesis of carbocyclic analogues of the mannosyl trisaccharide: ether- and imino-linked methyl 3,6-bis(5a-carba-α-d-mannopyranosyl)-3,6-dideoxy-α-d-mannopyranosides

Abstract Carbocyclic analogues 2 and 3 of the “trimannosyl structure 1”, methyl 3,6-bis(5a-carba-α- d -mannopyranosyl)-3,6-dideoxy-α- d -mannopyranosides bonded by way of respective ether and imino linkages, were synthesized. The ether 2 had no inhibitory activity against α- d -mannosidase; in contrast, the imino compound 3 was a mild inhibitor. Furthermore, the inhibitory activity of 4, related to 3 by introduction of unsaturation between C-5 and C-5a of the carba-sugar moieties, was shown to be somewhat greater.

Synthesis of glucosylceramide analogues: imino-linked 5a-carbaglycosylceramides, potent and specific glucocerebrosidase inhibitors

Imino-linked carbocyclic analogues (E)- and (Z)-2 of glucosylceramide 1 have been synthesized and shown to be potent and specific inhibitors against glucocerebrosidase.

[9] Chemical synthesis of glycosylamide and cerebroside analogs composed of carba sugars

Publisher Summary Many kinds of glycosylamides, glycolipid analogs structurally related to glycosphingolipids, and glycoglycerolipids, have been synthesized and subjected to several biological tests. Some compounds have been found to be immunomodulators, and among them, N-( β -D-glucopyranosyl)-Noctadecyldodecanamide produces a dose-dependent increase in the formation of antibodies against sheep erythrocytes in vitro in the concentration range 3–100 mg/ml. Although the biological functions of glycosphingolipids have been examined thoroughly in the chapter, in order to gain further understanding of their biological functions it is necessary to provide isomerically pure glycosphingolipids as well as structural analogs in larger quantities by chemical synthesis. The chapter describes a method for a synthesis of the imino-linked 5a-carba sugar analog of glucoceramide. The method combines the 1, 2-aziridinosphingosine derivatives with properly blocked 5a-carba-fl-o-glucopyranosylamine.