Rationally designed squaryldiamides – a novel class of sugar-nucleotide mimics?

Abstract

Sugar-nucleotides such as GDP-mannose, GDP-fucose and UDP-glucose are important biomolecules with a central role in carbohydrate and glycoconjugate biosynthesis, metabolism and cell signalling. Analogues and mimics of naturally occurring sugar-nucleotides are sought after as chemical tools and inhibitor candidates for sugar-nucleotide-dependent enzymes including glycosyltransferases. Many sugar-nucleotides bind to their target glycosyltransferases via coordination of the diphosphate group to a divalent metal cofactor in the active site. The identification of uncharged, chemically stable surrogates for the diphosphate group, with the ability to coordinate to a divalent metal, is therefore an important design criteria for the development of sugar-nucleotide mimics. Here, we describe the rational design and synthesis of a novel class of sugar-nucleotide mimics based on a squaryldiamide scaffold, an uncharged phosphate isostere. We demonstrate by comprehensive NMR titration experiments that the new sugar-nucleotide mimics coordinate efficiently to Mg(2+), and provide results from biological studies with a therapeutically relevant mannosyltransferase from Trypanosoma brucei. Our findings suggest that squaryldiamides are a promising template for the development of sugar-nucleotide mimics, and illustrate the considerable potential of the squarylamide group as a fragment for inhibitor design.

A novel route for preparing 5′ cap mimics and capped RNAs: phosphate-modified cap analogues obtained via click chemistry

“…3C). 35 5′-Azido-5′-deoxyguanosine ( 16a ) was synthesized from 5′-iodo-5′-deoxyguanosine 36,37 ( 21 ) and N 7 -methylated by methyl iodide in DMF to yield 5′-azido-7-methylguanosine ( 16b ) (Fig. 3D).…”

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

“…Although these phosphate groups harness favorable interactions with glycosyltransferases, they limit the ability of such inhibitors to permeate into cells. Efforts to circumvent this problem by generating donor analogs having pyrophosphate mimics have not met with great success 67,68 , leaving the glycosyltransferase field with a small repertoire of inhibitors able to act in cells. One interesting molecule with cellular activity is the widely used natural product tunicamycin (44).…”

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

“…To mimic the diphosphate section of UDP-sugars, squaric acid was used as it is a convenient phosphomimetic building block. 65 The squaramic acid series produced one inhibitor (66b) with an IC 50 of 174 ± 21 μM against the glycosyl transferase TcdB-GTD. 66, 67 The glycine inhibitor (68b) revealed an IC 50 of 35 ± 7 units with the acetyltransferase PglD.…”