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.

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The intrinsic complex nature of Contracts in the Energy sector leads to frequent international disputes. The complexity is generated by (i) the involvement of multiple stakeholders with potentially conflicting interests (Multinational Companies, State-Owned Companies, Host States and their citizens); (ii) transnational jurisdictions divergence (local laws, investor’s country laws, international practices and regulations); and (iii) changes in the laws and regulations over time (long-term nature of Energy contracts). Therefore, not surprisingly, traditional litigation in the Energy sector is often replaced with Alternative Dispute Resolution (ADR) through the recurrent application of Arbitration clauses. This article aims to improve dispute management in the Energy sector by encouraging best ADR practices. Modelling and Conceptual research approaches are adopted to encourage the introduction of the smart contract. The analyses triggered the drafting of a model for contractual automation. Recurring top clauses are mapped and associated with Equity solutions. Moreover, a comprehensive, efficient and feasible ‘Electronic ADR’ framework is shaped to prevent (or automatically settle) disputes in the Energy sector.