Michael acceptor molecules in natural products and their mechanism of action

Abstract

Purpose: Michael receptor molecules derived from plants are biologically active due to electrophilic groups in their structure. They can target nucleophilic residues on disease-related proteins, with significant therapeutic effects and low toxicity for many diseases. They provide a good option for relevant disease treatment. The aim of this study is to summarize the existing MAMs and their applications, and lay a foundation for the application of Michael receptor molecules in life science in the future.Methods: This review summarizes the published studies on Michael receptor molecules isolated from plants in literature databases such as CNKI, Wanfang Data, PubMed, Web of Science, ScienceDirect, and Wiley. Latin names of plants were verified through https://www.iplant.cn/. All relevant compound structures were verified through PubChem and literature, and illustrated with ChemDraw 20.0.Result: A total of 50 Michael receptor molecules derived from various plants were discussed. It was found that these compounds have similar pharmacological potential, most of them play a role through the Keap1-Nrf2-ARE pathway and the NF-κB pathway, and have biological activities such as antioxidant and anti-inflammatory. They can be used to treat inflammatory diseases and tumors.Conclusion: The Michael receptor molecule has electrophilicity due to its unsaturated aldehyde ketone structure, which can combine with nucleophilic residues on the protein to form complexes and activate or inhibit the protein pathway to play a physiological role. Michael receptor molecules can regulate the Keap1-Nrf2-ARE pathway and the NF-κB pathway. Michael receptor molecules can be used to treat diseases such as inflammation, cancer, oxidative stress, etc.

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

“…Due to their structure (overall electronic parameters, electron-withdrawing substituents, and conjugated –C(=O)–N(H)– bond), ring-substituted cinnamanilides are able to interact with a variety of biological targets in many signaling pathways in cells, as reported recently [ 12 , 13 , 30 , 63 , 64 , 65 ], and thus meet the requirement of being therapeutically useful multi-target agents. The theory of the dependence of activity on the ability of compounds to act as Michael acceptors would be clearly confirmed by the preparation and biological evaluation of hydrogenated analogues of active cinnamanilides.…”

“…Thus, 2 × 16 lipophilic compounds with electron-withdrawing substituents that cause electron deficiency throughout the conjugated double-bond system, including the amide group, were prepared. It can be stated that these designed agents meet the definition of so-called Michael acceptors, i.e., compounds in which generally double/triple bonds are conjugated with electron-withdrawing groups and which are able to react with nucleophiles, i.e., electron-rich substrates (e.g., NH or SH groups) [ 29 ], and thus have the ability to interact with many biological targets [ 12 , 13 , 30 ]. All the prepared compounds were tested against Gram-positive and mycobacterial strains and were also docked into the binding site of their potential intracellular target InhA, which has been previously reported to interact with similar compounds [ 31 , 32 , 33 ].…”

Discovery and Anti-Inflammatory Activity of a Cyanobacterial Fatty Acid Targeting the Keap1/Nrf2 Pathway

“…Kelch ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)−antioxidant response element (ARE) signaling is a key cytoprotective pathway involved in the induction of phase II detoxification enzymes and therefore protects cells from the accumulation of toxic metabolites [3]. Keap1, a negative regulator of Nrf2 in the cytoplasm, is a cysteine-rich protein (27 cysteine residues) and, upon alkylation of specific Cys residues (usually C151) by electrophiles, induces Nrf2 translocation to the nucleus, where it binds to the ARE and induces the expression of antioxidant genes (NQO1, HO-1) and suppresses NF-κB-dependent proinflammatory genes (iNOS, COX2) [3,[7][8][9][10]. Hence, the Keap1/Nrf2−ARE pathway is considered a promising therapeutic target for the management of several inflammatory and oxidative-stress-mediated diseases.…”

“…Among the well-established Nrf2 activators are molecules bearing an α,β-unsaturated carbonyl moiety [7,8]. They activate Nrf2 via electrophilic modification of cysteine residues on the Keap1 protein through the 1,4-conjugate addition (Michael) reaction [7,8].…”

“…Among the well-established Nrf2 activators are molecules bearing an α,β-unsaturated carbonyl moiety [7,8]. They activate Nrf2 via electrophilic modification of cysteine residues on the Keap1 protein through the 1,4-conjugate addition (Michael) reaction [7,8]. Their chemical reactivity and specific molecular architecture dictate the target profile in the cysteome within and beyond Keap1, producing a net effect.…”