Premium
Chemo‐Enzymatic Synthesis of Branched N ‐Acetyllactosamine Glycan Oligomers for Galectin‐3 Inhibition
Author(s) -
Laaf Dominic,
Steffens Hanna,
Pelantová Helena,
Bojarová Pavla,
Křen Vladimír,
Elling Lothar
Publication year - 2017
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201700969
Subject(s) - chemistry , glycan , galactose oxidase , reductive amination , stereochemistry , galactose , anomer , aldehyde , glycosyltransferase , biochemistry , combinatorial chemistry , enzyme , glycoprotein , catalysis
We present here a novel concept for the synthesis of branched N ‐acetyllactosamine (LacNAc) glycan structures. Through a combination of sequential enzymatic and chemical reactions of Leloir ‐glycosyltransferases, galactose oxidase and reductive amination, we obtained branched glycan oligomers with a variation of LacNAc and/or N′,N′′ ‐diacetyllactosamine (LacdiNAc) glycan epitopes. Incorporation of a branching point was accomplished by an optimized galactose oxidase protocol rendering the C‐6 aldehyde functionality at the terminal galactose of a LacNAc oligomer. After glycan chain elongation by glycosyltransferases, the C‐6 aldehyde‐containing linear building block was conjugated with amine‐linker functionalized glycans. Methanol and a temperature of 50 °C were found to be optimum conditions for the α‐picoline borane‐catalyzed reductive amination. Chemically branched glycans were obtained in high synthetic yields (≈81%) in preparative batches. Product isolation was accomplished by preparative HPLC with good overall yields (>60%). The structural integrity was proven by ESI‐MS and NMR. The herein synthesized branched LacNAc oligomers feature a variation of Lac(di)NAc epitopes and were confirmed to be potent inhibitors of human galectin‐3 (Gal‐3). The branched decasaccharide with two LacdiNAc‐LacNAc branches ranks among the most potent poly‐LacNAc‐based Gal‐3 inhibitors so far.