Development of a spectrophotometric method for assessment of the relative reactivity of monocarbonyl analogs of curcumin with 2-(dimethylamino)ethanethiol

Abstract

In order to improve the bioavailability of curcumin, studies have been undertaken to prepare the so-called monocarbonyl analogs of curcumin (MACs) and assess their biological activity. These analogs contain an electrophilic α,β-unsaturated carbonyl moiety (Michael acceptor). Several key biological processes are connected/controlled with thiol alkylation (glutathione, cysteine, cysteine peptide residues). The most likely reaction is the Michael addition between the α,β-unsaturated acceptor and a corresponding thiol. 2,6-Bisarylidenecyclohexanone and 3,5-bisarylidenepiperidin-4-one scaffolds offer convenient tunability of electrophilicity and redox properties of the Michael acceptor by the introduction of various substituents. In this study, several MACs were prepared by Claisen-Schmidt condensation reaction, and their reactivity with 2-(dimethylamino)ethanethiol was evaluated. For this purpose, based on the UV-Vis spectra of the analogs and thiol(s), a proper method for spectrophotometric evaluation of their reactivity with 2-(dimethylamino)ethanethiol was optimized. The relative reactivity of the analogs was 7 > 2 > 5 > 4 > 1 ≈ 6. The developed method is simple, and it can be extended to assess the reactivity of other MACs.

Experimental and theoretical studies on (2E,5E)-2,5-bis(2-methoxybenzylidene)cyclopentanone: Structural, electrochemical, spectroscopic features, solid-state interactions, molecular docking and adsorption studies onto 2D carbon nanomaterials

“…Our research groups have been involved in the synthesis and purification of these compounds and methodically exploring their biological activity. [16][17][18][19][20] For this study we have chosen the symmetrical (2E,5E)-2,5-bis(2-methoxybenzylidene)cyclopentanone (B2MBCP), because it has been evident from previous studies that MACs with methoxy and alkoxy groups, but without reactive phenolic OH group, have improved stability and biological activity. 12,21 The title compound represents the simplest cyclopentanone MAC with methoxy groups in the ortho position, where the influence on the dienone system will be the greatest.…”

Synthesis of Symmetrical Monocarbonyl Analogs of Curcumin Containing a 2-Bromobenzylidene Moiety and Spectrophotometric Assessment of Their Reactivity with 2-(Dimethylamino)ethanthiol

“…[21] and B2BrBC ((2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone) [22][23][24][25], have been extensively studied. Care needs to be taken when evaluating the properties and activities of these analogs because, similarly to curcumin [26], many of these cross-conjugated derivatives are pan-assay interference compounds (PAINS) [3,27].…”

“…In the past several years, our research efforts have been focused on the synthesis and experimental and theoretical studies of these ortho-substituted analogs [20,24,25,28,29]. We have established that symmetrical bis 2-fluorobenzylidene, 2-(trifluoromethyl)benzylidene and bis 2-bromobenzylidene derivatives are quite potent.…”

“…Additionally, we were inspired by the study of Fioravanti et al, who discovered that cyclic bis-(2-bromobenzylidene) compounds behaved as dual p300/CARM1 inhibitors and induced apoptosis in cancer cells [23]. Recently, we developed a spectrophotometric assay for the comparison of the reactivity of MACs towards thiol, and instead of commonly used cysteamine, we employed 2-(dimethylamono)ethanethiol (2DMAESH) [25].…”

“…MACs have especially pronounced biological activity when containing an electron-withdrawing group at the ortho-position of the benzene ring. Several derivatives, namely EF24 [15,16], C66 ((2E,6E)-2,6-bis[2-(trifluoromethyl)benzylidene]cyclohexanone) [17][18][19][20], Y20 ((2E,6E)-2-(2bromobenzylidene)-6-(2-(trifluoromethyl)benzylidene)cyclohexanone) [21] and B2BrBC ((2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone) [22][23][24][25], have been extensively studied. Care needs to be taken when evaluating the properties and activities of these analogs because, similarly to curcumin [26], many of these cross-conjugated derivatives are panassay interference compounds (PAINS) [3,27].…”