A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds
A simple theoretical calculation (reactivity of nitriles with methanethiol) was used to predict the electrophilicity of diverse nitrile warheads. These calculated electrophilicities were found to correlate with the extent of thiazoline adduct formed upon incubation of the nitriles with cysteine. Nit...
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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (4), p.998-1002 |
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Sprache: | eng |
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Zusammenfassung: | A simple theoretical calculation (reactivity of nitriles with methanethiol) was used to predict the electrophilicity of diverse nitrile warheads. These calculated electrophilicities were found to correlate with the extent of thiazoline adduct formed upon incubation of the nitriles with cysteine.
Nitrile-based inhibitors of cathepsin K have been known for some time and mechanism-of-action studies have demonstrated that cysteinyl proteases interact with nitriles in a reversible fashion. Three main classes of nitrile-containing inhibitors have been published in the cathepsin K field: (i) cyanamides, (ii) aromatic nitriles, and (iii) aminoacetonitriles. A computational approach was used to calculate the theoretical reactivities of diverse nitriles and this was found to correlate with their extent of reactivity with free cysteine. Moreover, there is a tentative link between high reactivity with cysteine and the potential to lead to irreversible covalent binding to proteins. |
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ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2006.11.044 |