Novel derivatives of ISO-1 as potent inhibitors of MIF biological function

Balachandran, Sarala; Rodge, Atish H.; Gadekar, Pradip K.; Yadav, Vitthal N.; Kamath, Divya; Chetrapal-Kunwar, Anshu; Bhatt, Pooja; Srinivasan, Shaila; Sharma, Somesh; Vishwakarma, Ram A.; Dagia, Nilesh M.

doi:10.1016/j.bmcl.2009.06.052

Cited by 21 publications

(20 citation statements)

References 9 publications

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“…27 In an independent assay of ISO-1 using DOPA, an IC 50 of >100 µM was reported; the discrepancy with the 7 µM value was suggested to arise from use of different concentrations of rhMIF. 28 We also find Orita-13 with a K i averaging 17 µM to be much less active than from the previously reported K i of 0.038 µM, again in a dopachrome assay. 16 Orita-13 would seem to be the most potent MIF inhibitor in the journal literature.…”

Section: Resultssupporting

confidence: 44%

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

et al. 2015

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Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl–aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.

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Section: Resultssupporting

confidence: 44%

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

et al. 2015

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“…The MIF tautomerase inhibitor was used intrathecally in this study to investigate the role of MIF in pain regulation, which was mainly based on the fact that the blockade of tautomerization could inhibit MIF biologic activities. 20,33 Consistently, spinal use of ISO-1 effectively attenuated CCIinduced pain behavioral responses and cellular changes that were identical to the effect of spinal MIF antibody. The intrathecal administration of drugs is an effective, promising method in pain study, 34 -36 but it is difficult to perform in clinical contexts to general physicians.…”

Section: Pain Medicinementioning

confidence: 71%

“…One major characteristic of MIF is the tautomerase activity, and blockade of this enzymatic activity can inhibit the biologic functions of MIF effectively. 20,33 In this study, we used ISO-1 as the inhibitor of MIF tautomerase activity. Therefore, the tautomerase activity of MIF was evaluated further through a modified assay reported in our previous work and elsewhere.…”

Section: Mif Tautomerizaiton and Rmif Activity Analysesmentioning

confidence: 99%

“…So, the designing of drugs focused on MIF tautomerization that could pass through the blood-cerebrospinal fluid barrier possesses pivotal clinical and pharmacological implications. 33 Neuroinflammation is an essential part contributing to the onset and development of pain through neural-immune interactions that activate immune cells, glial cells, and neurons, leading to the debilitating pain state. 60 Although persistent or recurring exposure of neurons to activated immune cells is related with an increase in painful behaviors, the knowledge of the functional consequences of immune cellneuron interaction is still incomplete.…”

Section: Pain Medicinementioning

confidence: 99%

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Spinal Macrophage Migration Inhibitory Factor Is a Major Contributor to Rodent Neuropathic Pain-like Hypersensitivity

Wang

Shen

et al. 2011

Anesthesiology

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“…Additionally, soluble CD74 molecules have been isolated in vitro . Secondly, there are now effective, small-molecule MIF antagonists available, with ISO-1 being the most widely accepted one [78, 108]. Based on these findings further small compound library screenings and computational drug design studies are now underway.…”

Section: Mif Brain Tumors Angiogenesis and Tumor Microenvironmentmentioning

confidence: 99%

Brain Miffed by Macrophage Migration Inhibitory Factor

Savaskan

Fingerle‐Rowson

Buchfelder

et al. 2012

International Journal of Cell Biology

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Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches.

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Novel derivatives of ISO-1 as potent inhibitors of MIF biological function

Cited by 21 publications

References 9 publications

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

Spinal Macrophage Migration Inhibitory Factor Is a Major Contributor to Rodent Neuropathic Pain-like Hypersensitivity

Brain Miffed by Macrophage Migration Inhibitory Factor

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