Chemo-Enzymatic Synthesis of Branched N-Acetyllactosamine Glycan Oligomers for Galectin-3 Inhibition

0483762 - MBÚ 2018 RIV DE eng J - Journal Article
Laaf, D. - Steffens, H. - Pelantová, Helena - Bojarová, Pavla - Křen, Vladimír - Elling, L.
Chemo-Enzymatic Synthesis of Branched N-Acetyllactosamine Glycan Oligomers for Galectin-3 Inhibition.
Advanced Synthesis & Catalysis. Roč. 359, č. 22 (2017), s. 4015-4024. ISSN 1615-4150. E-ISSN 1615-4169
R&D Projects: GA ČR GC15-02578J; GA MŠMT(CZ) LTC17005
Institutional support: RVO:61388971
Keywords : biomimetic synthesis * galectin-3 * glycosylation
OECD category: Biochemistry and molecular biology
Impact factor: 5.123, year: 2017

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 degrees C were found to be optimum conditions for the alpha-picoline borane-catalyzed reductive amination. Chemically branched glycans were obtained in high synthetic yields (approximate to 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.
Permanent Link: http://hdl.handle.net/11104/0278964