Synthesis and biological activity of novel MIF antagonists

Balachandran, Sarala; Gadekar, Pradip K.; Parkale, Santosh S.; Yadav, Vitthal N.; Kamath, Divya; Ramaswamy, Sneha; Sharma, Somesh; Vishwakarma, Ram A.; Dagia, Nilesh M.

doi:10.1016/j.bmcl.2010.12.127

Cited by 16 publications

(15 citation statements)

References 10 publications

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“…Upon release, MIF modulates the expression of several proinflammatory molecules, including cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8), nitric oxide, and COX2 24-26. Moreover, MIF is required for resistance to several pathogens that express TLR ligands.…”

Section: Introductionmentioning

confidence: 99%

MIF Synergizes with Trypanosoma cruzi Antigens to Promote Efficient Dendritic Cell Maturation and IL-12 Production via p38 MAPK

Terrazas¹,

Huitron²,

Vázquez³

et al. 2011

Int. J. Biol. Sci.

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Macrophage migration inhibitory factor (MIF) has been found to be involved in host resistance to several parasitic infections. To determine the mechanisms of the MIF-dependent responses to Trypanosoma cruzi, we investigated host resistance in MIF-/- mice (on the BALB/c background) during an intraperitoneal infection. We focused on the potential involvement of MIF in dendritic cell (DC) maturation and cytokine production. Following a challenge with 5 x 103 T. cruzi parasites, wild type (WT) mice developed a strong IL-12 response and adequate maturation of the draining mesenteric lymph node DCs and were resistant to infection. In contrast, similarly infected MIF-/- mice mounted a weak IL-12 response, displayed immature DCs in the early phases of infection and rapidly succumbed to T. cruzi infection. The lack of maturation and IL-12 production by the DCs in response to total T. cruzi antigen (TcAg) was confirmed by in vitro studies. These effects were reversed following treatment with recombinant MIF. Interestingly, TcAg-stimulated bone marrow-derived DCs from both WT and MIF-/- mice had increased ERK1/2 MAPK phosphorylation. In contrast, p38 phosphorylation was only upregulated in WT DCs. Reconstitution of MIF to MIF-/- DCs upregulated p38 phosphorylation. The MIF-p38 pathway affected MHC-II and CD86 expression as well as IL-12 production. These findings demonstrate that the MIF-induced early DC maturation and IL-12 production mediates resistance to T. cruzi infection, probably by activating the p38 pathway.

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Section: Introductionmentioning

confidence: 99%

MIF Synergizes with Trypanosoma cruzi Antigens to Promote Efficient Dendritic Cell Maturation and IL-12 Production via p38 MAPK

Terrazas¹,

Huitron²,

Vázquez³

et al. 2011

Int. J. Biol. Sci.

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“…To our surprise, however, literature regarding the construction of isoxazoles via 1,3-dipolar cycloaddition mostly described the use of readily available N-vinylpyrrolidone 8,10,28 or N-vinylphthalimide, 8 except for an isolated report describing the use of a cyclic enamide synthon 29 and a recent example involving enamides akin to 1, generated via a base-promoted isomerization of N-allylamides. 30 Thus, it appeared that a modular approach ( While the crude enamides were at least 85% pure by 1 H NMR spectroscopy, attempted use of this material in subsequent cycloaddition reactions unexpectedly delivered a complex mixture of products.…”

Section: -21mentioning

confidence: 99%

“…Strategies based on sequential MCRs introduce even more diversity elements which can be altered to fine-tune the compounds' desired biological activity and suppress side-effects. 5 Isoxazolines certainly deserve to be considered as privileged cores 6 for drug design, taking into account the multitude of biological targets, including tyrosine phosphatase 1B, 7 macrophage migration inhibitory factor (MIF), 8 fatty acid amide hydrolase (FAAH), 9 and M 1 muscarinic acetylcholine receptors, 10 which are perturbed by isoxazoline-based compounds. Replacement of the carbohydrate portion of nucleosides with an isoxazoline core delivered nucleoside analogs that inhibited viral reverse trascriptase.…”

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confidence: 99%

Convenient modular construction of medicinally important 5-acylamino-4,5-dihydroisoxazoles featuring four elements of diversity

Kulyashova

Krasavin

2016

Tetrahedron Letters

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“…15,20–23 Based on ISO-1, several other MIF inhibitors have been developed, among which are the biaryltriazoles. 24–28 Using a structure-based virtual screening method, Orita-13 containing a chromen-4-one scaffold was identified as MIF inhibitor. 26,29 Additionally, covalent MIF inhibitors have been described, such as TP, as probes suitable for activity-based protein profiling.…”

Section: Introductionmentioning

confidence: 99%

Discovery of chromenes as inhibitors of macrophage migration inhibitory factor

Kok

Wapenaar

Wang

et al. 2018

Bioorganic & Medicinal Chemistry

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Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

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Synthesis and biological activity of novel MIF antagonists

Cited by 16 publications

References 10 publications

MIF Synergizes with Trypanosoma cruzi Antigens to Promote Efficient Dendritic Cell Maturation and IL-12 Production via p38 MAPK

MIF Synergizes with Trypanosoma cruzi Antigens to Promote Efficient Dendritic Cell Maturation and IL-12 Production via p38 MAPK

Convenient modular construction of medicinally important 5-acylamino-4,5-dihydroisoxazoles featuring four elements of diversity

Discovery of chromenes as inhibitors of macrophage migration inhibitory factor

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