Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor [electronic resource]
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| Online Access: |
Online Access (via OSTI) |
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| Format: | Government Document Electronic eBook |
| Language: | English |
| Published: |
Washington, D.C. : Oak Ridge, Tenn. :
United States. Department of Energy. Office of Science ; distributed by the Office of Scientific and Technical Information, U.S. Department of Energy,
2015.
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| Subjects: |
| Abstract: | 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. We also show 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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| Item Description: | Published through SciTech Connect. 02/20/2015. Journal of the American Chemical Society 137 8 ISSN 0002-7863 AM. Pawel Dziedzic; José A. Cisneros; Michael J. Robertson; Alissa A. Hare; Nadia E. Danford; Richard H. G. Baxter; William L. Jorgensen. |
| Physical Description: | p. 2996-3003 : digital, PDF file. |