Synthesis method of tetrasaccharide MAG antagonist

Abstract

The invention discloses a synthesis method of a disialic acid tetrasaccharide MAG antagonist by a chemical enzyme process. The invention also discloses two intermediates for synthesizing and preparing a tetrasaccharide MAG antagonist, which are respectively compounds disclosed as general formulae IV and V. By combining the flexibility of the chemical synthesis process and the regioselectivity and high efficiency of the enzyme synthesis process, the method overcomes the defects of low substrate reaction activity, multiple synthesis steps and low yield in the chemically synthesized disialic acid tetrasaccharide MAG antagonist at present, and the defects of difficulty in obtaining sialyl transferase, only recognition of glycopeptide and the like in the enzyme process, and has the advantages of high substrate reaction activity and high yield. Therefore, the method has important meanings in researching interactions between the sialic acid antagonist and the myelin related glycoprotein on the molecular level.

Description

technical field [0001] The invention relates to a chemical and enzymatic synthesis method of a tetrasaccharide antagonist specifically combined with myelin-associated glycoprotein (MAG), and belongs to the field of carbohydrate drugs. Background technique [0002] Myelin-associated glycoprotein (MAG) is distributed on the myelin sheath that contacts axons in the central nervous system (CNS), and it promotes developing neurons and inhibits mature neurons. MAG is a sialic acid-binding protein that binds to sialoglycoproteins and sialoglycolipids (gangliosides) at the arginine 118 (Arg118) on the first immunoglobulin-like domain ). The study found that the removal of sialic acid on the surface of neurons by neuraminidase blocked the inhibitory effect of MAG on neuronal neurite outgrowth, and demonstrated that the gangliosides GDla and GTlb with sialic acid act as receptors in neurons to mediate Inhibition of MAG (R.H.Quarles, J.Neurochem., 2007, 100, 1431–1448; N.R.Mehta, T.N...

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Problems solved by technology

The chemoenzymatic synthesis of tetrasaccharide antagonists reported in the literature currently uses mammalian-derived sialyltransferases to catalyze the introduction of two different sialic acids, but mammalian-derived sialyltransferases are used to synthesize tetrasaccharides Faced with the following two difficulties: 1. Mammalian-derived sialyltransferases are all transmembrane proteins, which are difficult to express, and it is difficult to obtain a certain amount of soluble protein; 2. This series of enzymes often have strong substrate specificity , narrow substrate applicability, for example, the mammalian source sialyltransferases used in current literature reports only have high reactivity to glycopeptides (O.Blixt, K.Allin, L.Pereira, A.Datta, and J .C. Paulson, J. Am. Chem. Soc., 2002, 124, 5739-5746)

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