Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Abstract

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

Synthesis of Nitrogen‐Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells

“…Because the Michael acceptor site is responsible for goniothalamin′s activity, we synthesized compounds 13 d – g to investigate the influence of a second Michael acceptor group on cytotoxic activity. Although the idea of covalent modifiers as biologically active substances has been initially avoided by the pharmaceutical industry due to the possible off‐target action, the insertion of Michael acceptor moieties has resulted in promising active molecules, particularly for cancer treatment . While compound 13 d and 13 e were obtained in moderate to good yields, the reaction using α‐bromoacrylic acid furnished a mixture of the desired product 13 f and the 2,3‐dibromopropanamide analogue, and the α‐fluoroacrylic acid was found to be unstable under the reaction conditions.…”

Helenalin Analogues Targeting NF‐κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles

“…First-order reaction kinetics is atypical for thiol-Michael addition reactions. [5,14] Differences in compound structures and/or assay conditions (e.g., pH and the type of thiol evaluated) may likely explain the discrepancy. For example, in previous studies with helenalin, cysteine had the reverse reactivity of GSH in which addition to the α-methylene-γ-butyrolactone occurred first and was complete in less than five minutes.…”

“…[4] Specifically, chemical probes and therapeutic molecules have been designed to have thiol reactive Michael acceptors to gain potency, selectivity, and overcome biological resistance. [5] Natural products have provided a rich source for cysteine reactive covalent modifiers that inhibit specific classes of proteins, many of which contain a α-methylene-γ-butyrolactone. [6] Helenalin is a pseudoguaianolide natural product isolated from plants in the Arnica and Helenium genera that is a covalent protein modifier (Figure 1).…”

Targeting pharmacophore with probe‐reactivity‐guided fractionation to precisely identify electrophilic sesquiterpenes and its activity of anti‐TNBC

“…Thus, through Michel's reaction, ESs with specific electrophilic groups alkylate the enzymes or transcription factors, regulate key cellular signal pathways, and then produce anti‐TNBC activity . Targeted covalent modification has emerged as a validated approach to drug discovery with the recent US Food and Drug Administration (FDA) approvals of afatanib (2013), ibrutinib (2013), and osimertinib (2015) drugs that were designed to undergo an irreversible hetero‐Michael addition reaction with a unique cysteine residue of a specific protein …”