Glycans play diverse and important roles in biological systems. Glycosyltransferases are key enzymes in the biosynthesis of glycans catalyzing the specific transfer of carbohydrate moieties from an activated donor (nucleotide-diphosphate-sugar) to a specific acceptor substrate. The human galactosyltransferase B (GTB) is responsible for the transfer of an a-D-galactose residue from UDP-galactose to the H-antigen yielding the blood group B antigen. Pancreatic tumors are much more prevalent in persons with blood group B than in those with other blood groups. Therefore GTB inhibitors promise to be important tools to regulate cancer progression. Rational design of an inhibitor was achieved using the crystal structure of GTB with bound donor and acceptor substrate. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/240nm/uploads/33293_gk_poster_abstract_figure_3-4-10.jpg' alt='' /> Here, we report the design and synthesis of a modified linker replacing the pyrophosphate and the ribose residues to optimize the pharmacokinetic and pharmacodynamic properties of the inhibitor. In silico studies showed that a sulfone can act as a good binder to the manganese ion present in the enzyme. The synthesis of this donor substrate inhibitor will be discussed along with affinity data.

Towards glycosyltransferase inhibitors: Non ionic replacements for the diphosphate of sugar nucleotides

247th National Meeting (2014)

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