Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice

Garai, János; Radnai, B; Vámos, Eszter; Kovács, Dominika; Vántus, Viola Bagóné; Rumbus, Zoltán; Pákai, Eszter; Garami, András; Gulyás-Fekete, Gergely; Agócs, Attila; Krekó, Marcell; Zaman, Khadiza; Prókai, László; Őrfi, László; Jakus, Peter; Lóránd, Tamás

doi:10.1016/j.ejmech.2022.115050

Cited by 3 publications

(5 citation statements)

References 62 publications

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“…Macrophage activation was examined by measuring reactive oxygen species (ROS) production, as previously published [49]. Shortly, RAW264.7 cells were plated onto 96well plates at a density of 10 5 cells/well 24 h prior to treatment.…”

Section: Determination Of Rosmentioning

confidence: 99%

“…The complete blockade of MIF function is rather unfavorable, since MIF has protective roles during the resolution of inflammation [46] or tissue repair [47], suggesting specific activities need to be targeted, but not MIF in general. MIF also promotes an important tautomerase activity (IUBMB Enzyme Nomenclature: EC 5.3.2.1) [48,49] by catalyzing the tautomeric keto-enol transformation of several substrates such as keto-phenyl-pyruvate to enol-phenyl-pyruvate and vice versa. Accordingly, the tautomeric activity can be divided into enolase and ketonase sub-activities [50,51].…”

Section: Introductionmentioning

confidence: 99%

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Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Vámos,

Kálmán,

Sturm

et al. 2023

Antioxidants

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Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production and acceleration of glycolysis. Macrophage migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase and enolase), was discovered to regulate M1 polarization. Here, we reveal that KRP-6, a potent and highly selective MIF ketonase inhibitor, reduces MIF-induced human blood eosinophil and neutrophil migration similarly to ISO-1, the most investigated tautomerase inhibitor. We equally discovered that KRP-6 prevents M1 macrophage polarization and reduces ROS production in IFN-γ-treated cells. During metabolic reprogramming, KRP-6 improved mitochondrial bioenergetics by ameliorating basal respiration, ATP production, coupling efficiency and maximal respiration in LPS+IFN-γ-treated cells. KRP-6 also reduced glycolytic flux in M1 macrophages. Moreover, the selective MIF ketonase inhibitor attenuated LPS+IFN-γ-induced downregulation of PARP-1 and PARP-2 mRNA expression. We conclude that KRP-6 represents a promising novel therapeutic compound for autoimmune diseases, which strongly involves M1 macrophage polarization.

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Section: Determination Of Rosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Vámos,

Kálmán,

Sturm

et al. 2023

Antioxidants

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“…These two moieties were identified as the crucial interaction in acetylcholinesterase (AChE) inhibition. [20,25] The indanone moiety is also been studied as a drug moiety against other targets such as anti-inflammatory, [26] other neurodegenerative/ neuroinflammation pathways, [27] and anti-cancer properties. [28] Although naturally existing phenolic compounds such as coumaric acid, caffeic acid, and sinapic acid in dietary supplements were studied to be beneficial to AD, [29][30][31][32] the studies of the possible synergism activity of phenolic moiety and existing drug fragment as an MTDL are still limited.…”

Section: Introductionmentioning

confidence: 99%

“…These two moieties were identified as the crucial interaction in acetylcholinesterase (AChE) inhibition [20,25] . The indanone moiety is also been studied as a drug moiety against other targets such as anti‐inflammatory, [26] other neurodegenerative/ neuroinflammation pathways, [27] and anti‐cancer properties [28] …”

Section: Introductionmentioning

confidence: 99%

“…[28] Although naturally existing phenolic compounds such as coumaric acid, caffeic acid, and sinapic acid in dietary supplements were studied to be beneficial to AD, [29][30][31][32] the studies of the possible synergism activity of phenolic moiety and existing drug fragment as an MTDL are still limited. [26][27][28] This study investigates the potential anti-AD MTDL of hybrids consisting of a donepezil fragment and phenolic compounds.…”

Section: Introductionmentioning

confidence: 99%

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The Discovery of Benzylidene‐Indenone as Selective Butyrylcholinesterase Inhibitor with Choline Acetyltransferase Gene and Neurite Promoting Abilities

Ooi,

San Tang,

Tan

et al. 2024

ChemistrySelect

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Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disease, associated with aging. A total of forty benzylidene‐indenone derivatives were synthesized in search of multi‐target‐directed ligands (MTDL) against AD. Compound 9 was found as the most promising MTDL in this study. It was demonstrated to selectively inhibit human butyrylcholinesterase, increase the gene expression of choline acetyltransferase (CHAT), and promote neurite outgrowth in SH‐SY5Y cells. The compound was also predicted to be able to permeate across the lipid‐infused bilayer, indicating its ability to cross the blood‐brain barrier. The abovementioned findings show compound 9 and its analogs warrant further exploration as potential MTDL anti‐AD agents.

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(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4′-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs

Kenari,

Pintér,

Molnár

et al. 2024

IJMS

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Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.

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Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice

Cited by 3 publications

References 62 publications

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

The Discovery of Benzylidene‐Indenone as Selective Butyrylcholinesterase Inhibitor with Choline Acetyltransferase Gene and Neurite Promoting Abilities

(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4′-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs

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