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Description
Monocarbonyl analogs of curcumin have attracted attention due to their diverse biological activity. They contain a cross-conjugated α,β-unsaturated enone system. The cyclic derivatives possess two exocyclic C=C bonds, conjugated with the central carbonyl group, and they are well-suited to act as Michael acceptors for biologically relevant thiols. One of the key lead compounds is EF24, or (3E,5E)-3,5-bis(2-fluorobenzylidene)piperidin-4-one, with a cross-conjugated α,β-unsaturated ketone system. In this work computational methods were used to investigate the electronic characteristics of EF24 and other related MACs and their possible Michael-type reaction with N-acetylcysteine (NAC), selected as a representative thiol-containing biomolecule.
Calculations were done in HyperChem using the PM3 method, analyzing optimized EF24 and related MACs, neutral NAC (NAC–SH), its thiolate form (NAC–S⁻), and the MACs–NAC adduct. HOMO/LUMO energies, HOMO-LUMO gap and dipole moment were used as semiempirical descriptors to assess MACs electrophilicity and the nucleophilic behavior of NAC, particularly in its thiolate form.
The analysis focused on the LUMO distribution of EF24, particularly at the β-carbon atoms of the exocyclic C=C bonds, which were considered the most probable sites for nucleophilic sulfur attack. The HOMO of NAC–S⁻ was examined to confirm the localization of electron density on the sulfur atom. Compared with neutral NAC–SH, which showed weaker nucleophilic character, NAC–S⁻ was identified as the more reactive species involved in the proposed Michael-type addition. Therefore, the interaction between the HOMO of NAC–S⁻ and the LUMO of EF24 was used as the main basis for explaining the EF24–NAC interaction.
Keywords: MACs, EF24, N-acetylcysteine, Michael acceptor, HOMO-LUMO, PM3, thiol addition
References:
1. Clariano, M.; Marques, V.; Vaz, J.; Awam, S.; Afonso, M. B.; Perry, M. J.; Rodrigues, C. M. P. Monocarbonyl Analogs of Curcumin with Potential to Treat Colorectal Cancer. Chem. Biodiversity 2023, 20, e202300222. https://doi.org/10.1002/cbdv.202300222.
2. Ting, J. Y. C.; Roseli, R. B.; Krenske, E. H. How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin. Org. Biomol. Chem. 2020, 18, 1426–1435. https://doi.org/10.1039/C9OB02709B.