An NMR Spectroscopic Method to Identify and Classify Thiol‐Trapping Agents: Revival of Michael Acceptors for Drug Discovery?

Avonto, Cristina; Taglialatela‐Scafati, Orazio; Pollastro, Federica; Minassi, Alberto; Marzo, Vincenzo Di; Petrocellis, Luciano De; Appendino, Giovanni

doi:10.1002/anie.201005959

Cited by 152 publications

(168 citation statements)

References 37 publications

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“…To enhance our understanding of the binding mode between synthesized ligands and the receptor (reversible vs. irreversible labeling), we performed the model Michael addition reactions between acrylate derivative (4a) and thiols like cysteamine and N-acetylcysteine using the reported procedure [16]. Thus, 4a was dissolved in DMSO-d 6 , the 1 H NMR spectrum was recorded (Figure 2b), and then two equivalents of cysteamine were added and the spectrum recorded after 5 min (Figure 2c).…”

Section: Chemistrymentioning

confidence: 99%

“…Thus, the ability of salvinorin A-derived Michael acceptors to form covalent bonds may be advantageous for probing the affinity to the KOR. Considering the fact that Michael acceptors may also react reversibly with nucleophiles [15][16][17][18][19], such compounds may provide potential drug candidates for CNS disorders. Herein, we report the synthesis of a new series of potential Michael acceptor-type salvinorin A derivatives modified at C-2, a position that has been found to be crucial for a high-affinity binding to the KOR [3].…”

Section: Introductionmentioning

confidence: 99%

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Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR. Supporting informationScatter plot of pK i vs. pIC 50 at KOR for salvinorin A and tested analogs, 1 H, 13 C NMR spectra and chromatographic (HPLC) data for synthesized compounds 4a-4h and 5a-5n are presented in the Supporting Information.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Polepally¹,

Setola²,

Vardy³

et al. 2012

Planta Med

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“…Moreover, we also investigated the possible action mode of the active hit 8a in a thiol-sensitive assay using an NMR method, which was developed by Appendino G. et al 23 . The method was proved effective for identifying Michael acceptors, and sorting them into reversible and irreversible thiol sinks.…”

Section: Resultsmentioning

confidence: 99%

Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

Deng

Kong

Zhao

et al. 2012

Nat. Prod. Bioprospect.

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Abstract:A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated. Starting from fifteen structurally diverse natural products, a focused library featured by Michael acceptors is constructed with IBX mediated oxidation. Biological assay on five tumor cell lines indicates that four Michael acceptors, 8a, 11a, 12a, 14a, are with improved cytotoxicity (3-10 folds more potent than the parent compounds), which merit further investigations. Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor. The results suggest that the strategy is not only effective and relatively high discovery rate (28%), but also resource saving.

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“…1 H NMR studies with different α,β-unsaturated natural products have been used to successfully group these into reversible and irreversible thiol sinks. 11 Under the conditions used (DMSO-d 6 /dilution with CDCl 3 ) there is no need for a chromophore and important structural information is gained when more than one reactive site could be addressed in one molecule. On the other hand, to quantitatively compare libraries of compounds like chalcones where only small structural changes are introduced, our method allows for a very precise assessment of the reactivity of each single compound.…”

Section: Communication Organic and Biomolecular Chemistrymentioning

confidence: 99%

Reactivity assessment of chalcones by a kinetic thiol assay

et al. 2013

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The electrophilic nature of chalcones (1,3-diphenylprop-2-en-1-ones) and many other α,β-unsaturated carbonyl compounds is crucial for their biological activity, which is often based on thiolmediated regulation processes. To better predict their biological activity a simple screening assay for the assessment of the secondorder rate constants (k 2 ) in thia-Michael additions was developed.Hence, a clear structure-activity relationship of 16 differentially decorated hydroxy-alkoxychalcones upon addition of cysteamine could be established. Moreover, amongst other naturally occurring α,β-unsaturated carbonyl compounds k 2 values for curcumin and cinnamaldehyde were gained while cinnamic acids or esters gave no or very slow reactions.Chalcones (1,3-diphenylprop-2-en-1-ones) are natural products from the class of plant polyphenols and the biochemical precursors of cyclic flavonoids. They display anti-inflammatory, antioxidative, anti-mitotic, bactericidal, antifungal, antimalarial, antileishmanial to chemoprotective and chemopreventive activity, but also cytotoxic and antiviral properties were found. 1 Their activity is mostly based either on the Michael acceptor activity of the α,β-unsaturated carbonyl system, or their radical scavenging or reductive potential which are often referred to as antioxidative behaviour.2 The Michael acceptor activity is affected both by the decoration of the aromatic rings, and also, even more effectively, by an α-X-substitution of the double bond of the enone system. 3 Despite the fact that Michael acceptors are a neglected class of compounds in drug development their unique capability to address certain cysteine residues qualifies them as valuable tools to modulate biological activity. 1d Nevertheless, there is no simple, efficient quantitative method to assess and compare the reactivity of different chalcones and other α,β-unsaturated carbonyl compounds to be able to identify suitable electrophiles. Therefore, we developed a facile screening assay to determine the second-order rate constants (k 2 ) of chalcones in thia-Michael additions. As a starting point, the reactivity of the α-H-chalcones was assessed since this is the pattern found in almost all natural products of this class -the only exception being the α-hydroxychalcones.

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An NMR Spectroscopic Method to Identify and Classify Thiol‐Trapping Agents: Revival of Michael Acceptors for Drug Discovery?

Cited by 152 publications

References 37 publications

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

Reactivity assessment of chalcones by a kinetic thiol assay

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