Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?

Abstract

Michael acceptors represent a class of compounds with potential anti-cancer properties. They act by binding to nucleophilic sites in biological molecules, thereby disrupting cancer cell function and inducing cell death. This mode of action, as well as their ability to be modified and targeted, makes them a promising avenue for advancing cancer therapy. We are investigating the molecular mechanisms underlying Michael acceptors and their interactions with cancer cells, in particular their ability to interfere with cellular processes and induce apoptosis. The anti-cancer properties of Michael acceptors are not accidental but are due to their chemical structure and reactivity. The electrophilic nature of these compounds allows them to selectively target nucleophilic residues on disease-associated proteins, resulting in significant therapeutic benefits and minimal toxicity in various diseases. This opens up new perspectives for the development of more effective and precise cancer drugs. Nevertheless, further studies are essential to fully understand the impact of our discoveries and translate them into clinical practice.

Keywords: Michael acceptor compounds; chemotherapy; neoplastic metabolism.

Figure 1

Michael reaction utilizing different (pro-)nucleophiles.

Figure 2

Michael acceptor groups.

Figure 3

Michael donor groups.

Figure 4

MA reaction with the thiol group of cysteines in Keap1 protein.

Figure 5

Mechanism of reversible and irreversible covalent inhibitors.

Figure 6

Mechanism of reversible inhibition by conjugate addition to cyano acrylamides.

Figure 7

Mechanism of irreversible inhibition by conjugate addition to acrylamides.

Figure 8

Molecular structures of tyrosine kinase inhibitors.

Figure 9

Molecular structures of CDK inhibitors.

Figure 10

Molecular structure of Hesperadin.

Figure 11

Molecular structures of BTK inhibitors.

Figure 12

Endogenous nitration of UFAs.

Figure 13

NO₂-FAs reaction with the thiol group of biologically relevant proteins.

Figure 14

Molecular structures of anthracyclines.

Figure 15

Molecular structures of SINEs.

Figure 16

Piperlongumine and piperine molecular structure.

Figure 17

Sinomenine molecular structure.

Figure 18

Zerumbone and Eupalinolide J molecular structure.

Figure 19

Yuanhuacine molecular structure.

Figure 20

Celastrol molecular structure.

Figure 21

Physalin A molecular structure.

Figure 22

Withaferin A molecular structure.

Figure 23

Glycyrrhizinic acid molecular structure.

Figure 24

Fucoxanthin molecular structure.

Figure 25

Astaxanthin molecular structure.

Figure 26

Bioactivity of ASX.

Figure 27

α-acids and β-acids molecular structures.

Figure 28

Molecular structures of Annonacin, Annonin, Bullatacin and Uvaricin.

Figure 29

Leptomycin B molecular structure.

Figure 30

Molecular structure of CAPE, DA, CGA and RA.

Figure 31

Trans and cis isomers of the basic chalcone skeleton.

Figure 32

Molecular structure of Xanthohumol, Brussochalcone A, Brussochalcone B and Licochalcone A.

Figure 33

Molecular structure of Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin.

Figure 34

Tautomerism of curcumin.

Figure 35

Michael acceptor moieties in flavonoids.

Figure 36

Flavones in Scutellaria baicalensis extract.

Figure 37

Coumarin structure.

Figure 38

Classification of coumarins according to their chemical structure.

Figure 39

Chemical structures of Esculetin, Grandivitine, Agasiline and Aegelinol benzoate.