Seite - (000066) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.3: A) Thiol reactivity of electron-deficient olefins; B) Reversible covalent inhibitors that selectively target the non-catalytic cysteine-436 present in the C-terminal domain of the p90 ribosomal protein S6 kinase RSK2. The reversibility of thiol addition to electron-deficient olefins relates to the propensity of the resulting adduct to undergo β-elimination via an E1cB mechanism (Fig. 1.2.4). A kinetic study to determine the β- elimination rates of BME from the adduct highlighted the structural features required to design reversible covalent inhibitors (Krishnan, 2014). Remarkably, the rates were shown to correlate inversely with the computed proton affinity of the corresponding carbanions, suggesting that the acidity of the proton at the α-position of the adduct provides the driving-force for the β-elimination (Fig. 1.2.4). In this way, a feasible method is now available to fine-tune the intrinsic reversibility of the thiol-Michael reaction in a predictable way.