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

doi:10.1016/j.bmcl.2009.06.052

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 16, 15 August 2009, Pages 4773-4776

https://doi.org/10.1016/j.bmcl.2009.06.052 Get rights and content

Abstract

A series of novel 1,2,4-oxadiazole, phthalimide, amide and other derivatives of ISO-1 were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds inhibited MIF enzymatic activity at levels better than ISO-1. Of note, compounds 7, 22, 23, 24, 25 and 27 inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells and, more importantly, inhibited the MIF-induced production of interleukin-6 (IL-6) and/or interleukin-1β (IL-1β) significantly better than ISO-1.

Graphical abstract

Section snippets

Acknowledgment

We are thankful to Professor John R. David (Harvard School of Public Health) for critical review of this manuscript and insightful comments.

References and notes (9)

Y. Al-Abed et al.
J. Biol. Chem.
(2005)
Z. Jakopin et al.
Tetrahedron Lett.
(2007)
N.M. Dagia et al.
Eur. J. Pharmacol.
(2009)
O. Flieger et al.
FEBS Lett.
(2003)

There are more references available in the full text version of this article.

Cited by (23)

Irregularities in enzyme assays: The case of macrophage migration inhibitory factor
2016, Bioorganic and Medicinal Chemistry Letters
Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamined by synthesis, assaying for tautomerase activity, and protein crystallography. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, solubility issues, and especially covalent inhibition. Incubation time variation shows that 3, 4, 6, and 9 are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that the twice-discovered 3 is a covalent inhibitor.
Vitamin E is a MIF Inhibitor
2012, Biochemical and Biophysical Research Communications
Citation Excerpt :
Notably, the major contribution to the docking score for ISO-F comes from a hydrogen bond with an essential residue of MIF at LYS32 and ASN97 [13]. In our earlier studies, we have demonstrated that it is important for potential MIF inhibitors to block the biological function of MIF [13–15]. Accordingly, we next probed whether Vitamin E could block the purified human MIF-induced expression of pro-inflammatory cytokines.
Macrophage migration inhibitory factor (MIF) is known to contribute to the pathogenesis of inflammatory hyperalgesia and neuropathic pain. Prior studies have shown that Vitamin E treatment is associated with attenuated hyperalgesia and reduced neuropathic pain in rodents. Given these observations, we investigated the possibility that Vitamin E is a MIF inhibitor. Dopachrome tautomerase assays revealed that Vitamin E inhibits the enzymatic activity of purified human recombinant MIF (rhMIF) in a dose-dependent manner (45%, 74%, 92% and 100% inhibition at 3, 10, 30 and 100 μM, respectively). Cell-free ELISA based assays showed that Vitamin E binds onto rhMIF thereby blocking its recognition (48% inhibition at 100 μM). Circular dichroism studies indicated the Vitamin E has a strong affinity to bind to rhMIF (binding constant 19.52 ± 1.4 μM). In silico studies demonstrated that Vitamin E docks well in the active site of MIF with the long aliphatic chain of Vitamin E exhibiting strong van der Waals interactions with MIF. Most importantly, human cell-based assays revealed that Vitamin E significantly inhibits rhMIF-induced production of pro-inflammatory cytokines in a dose-dependent manner (77%, 80%, and 96% inhibition of IL-6 production, respectively, at 10, 30 and 100 μM). Taken together, these results demonstrate that Vitamin E inhibits not only the enzymatic activity of MIF but more importantly the biological function of MIF. Our findings suggest that Vitamin E may be attenuating hyperalgesia and reducing neuropathic pain at least in part by inhibiting MIF activity.
Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent
2011, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Therefore, molecule which will inhibit MIF activity will be of great value to combat above-mentioned MIF-mediated inflammation. After consideration of a series of heterocycles as a core structure, the 3,5-disubstituted isoxazoline was selected for further studies, because it is evident from literature that the molecules having isoxazoline skeleton are in general the potent MIF-inhibitor.20–26 Here, we report the synthesis and evaluation of such small molecules having isoxazoline skeleton that inhibit the tautomerase activity of human MIF (huMIF).
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is involved in the development of an array of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis and sepsis. The synthesis of MIF-inhibitor is a rationale approach to develop novel anti-inflammatory agent to treat multitude of inflammatory diseases. In this work, we have synthesized and evaluated MIF-inhibitory activity of a series of small molecules containing isoxazoline skeleton. Mode of binding of this inhibitor to human MIF (huMIF) was determined by docking studies. The synthesized molecules inhibit tautomerase activity of huMIF. The anti-inflammatory activity of the most active inhibitor, 4-((3-(4-hydroxy-3-methoxyphenyl)-4, 5-dihydroisoxazol-5-yl) methoxy) benzaldehyde (4b) was evaluated against huMIF-induced inflammation in a cellular model (RAW 264.7 cell). Compound 4b significantly inhibits huMIF-mediated NF-κB translocation to the nucleus, up-regulation of inducible nitric oxide synthase and nitric oxide production in RAW 264.7 cell which are the markers for inflammation. The compound 4b is not cytotoxic as evident from cell viability assay. Hence, the compound 4b has potential to be a novel anti-inflammatory agent.
Synthesis and biological activity of novel MIF antagonists
2011, Bioorganic and Medicinal Chemistry Letters
Two series of novel furan and indole compounds were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds from both series inhibited the enzymatic activity of MIF at levels equal to or significantly better than ISO-1 (an early MIF inhibitor). The majority of the compounds that robustly inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells were from the furan series (compounds 5, 9, 13, 15, and 16). In contrast, compounds that markedly inhibited the MIF-induced production of pro-inflammatory cytokines were predominantly from the indole series (compounds 26, 29, and 32).
Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action
2010, Journal of Biological Chemistry
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC₅₀ values in the range of 0.2–15.5 μm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro¹; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease.
Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity
2011, Anesthesiology
Citation Excerpt :
The results of our study showed spinal MIF could be inhibited by intrathecal MIF tautomerase inhibitor ISO-1, and indicated that it might be a unique target of pharmacological treatment. 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
Neuropathic pain-like hypersensitivity evoked by peripheral nerve injury is a salient clinical feature of pathologic pain; however, the underlying mechanisms of this condition remain largely unknown. Previous work has confirmed that spinal macrophage migration inhibitory factor (MIF) contributes to the pathogenesis of formalin-induced inflammatory hyperalgesia, but the role for MIF in neuropathic pain is still not well defined.
After approval by the Ethical Committee of Animal Use and Care, the sciatic chronic constriction nerve injury-induced rodent model of neuropathic pain was built. The mechanical threshold with von Frey hairs and thermal latency with hot plate were measured, and the expression of spinal MIF, CD74, and downstream extracellular signal-regulated kinase 1/2 signaling cascade was detected. Finally, MIF gene mutation and exogenous recombinant MIF were used for further clarification.
Intrathecal MIF tautomerase inhibitor reversed sciatic chronic constriction nerve injury-induced pain behaviors. The expression of MIF and CD74 up-regulated in a time-dependent manner in the ipsilateral spinal cord dorsal horn. These changes were associated with the activation of extracellular signal-regulated kinase 1/2 signaling by MIF/CD74 interaction, which subsequently led to up-regulatoin of interleukin-8 and N-methyl-d-aspartic acid receptor expression and additional production of prostaglandin E₂. Further, MIF gene mutation and exogenous recombinant MIF could desensitize and mimic sciatic chronic constriction nerve injury-evoked pain responses and cellular changes, respectively.
MIF-associated extracellular signal-regulated kinase 1/2-N-methyl-d-aspartic acid receptor or prostaglandin E₂ cascade accounts for the changes in peripheral nerve injury-induced nociceptive responses.

View all citing articles on Scopus

View full text

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

Abstract

Graphical abstract

Section snippets

Acknowledgment

J. Biol. Chem.

Tetrahedron Lett.

Eur. J. Pharmacol.

FEBS Lett.