Mechanism-based design of bioactive cyclopropanated sugars

Carbohydrates are important feed stocks in synthesis of natural products and so attract the interest of many organic researchers throughout the world, most notably in the last 10 years. The work described within explores the manipulation of the glucose-derived glucal. The addition of a reactive substituted cyclopropane across the alkene has been employed synthetically for many years, the subsequent ring breaking/expansion has been identified in the lab as slow and needing the support of catalysts. We ask the question, “Will cyclopropanated carbohydrates undergo the slow ring breaking/expansion in the presence of proteins, and are we able to identify which of the two types of mechanisms the reaction is going through?” The cyclopropane will act as a warhead to bind to proteins through Ferrier like rearrangements, resulting in irreversible inhibition. To identify the potential of such compounds, a combination of techniques are used to identify potential pathways, protein targets and reactivity through structure activity relationships.  The key steps involved in finding out the potential of cyclopropanated carbohydrates are to determine biological activities through bio-assays, structure activity relationships, selective binding, chemical genetics and chemical proteomics. The bio-assays together with structure activity relationships provides evidence on which chemical mechanism is occurring when the biological target is interacting with the bioactive cyclopropanated carbohydrates. The most active compound, benzose (7), was subjected to chemical genetic analysis to determine the pathways and processes that are involved with the mode of action. The chemical genetic analysis was complimented by chemical proteomics to identify the direct biological target. Analogues of benzose were synthesised by the addition of azide groups to undergo a Huisgen Cyclisation within a cell lysate to facilitate binding to an alkyne-substituted matrix.