Peptidyl-prolyl-cis/trans isomerases (PPIases) catalyze the rotation bout the imidic peptide bond in front of proline. Substances that act as PPlase inhibitors are considered as potential chemotherapeutics in the treatment of diseases with errors in the regulation of cell proliferation. Thus, PPIases emerged as promising targets in anticancer drug development.[figure1.jpg]Guided by the idea that compounds, which mimic the transition state 1   of the enzymatic rotation about the peptidic bond in front of proline, may act as PPlase inhibitors, we synthesized a series of aryl indanyl ketones 2  and aryl hetaryl ketones 3 and investigated their ability to inhibit Pin1 and cyclophilin.Indeed, remarkable reversible inhibition of the PPIases Pin1 and cyclophilin by ketones 2  and 3  was detected. The cell-penetrating ketones displayed Ki values in the mono-digit micromolar range or lower.1 A surprising selectivity in binding toward the iso-forms of cyclophilins was observed.2 In addition, we have identified a non-immunosuppressive ketone 2  which does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis.3[1] T. Hediger, W. Frank, M. Schumann, G. Fischer, M. Braun, Chem. Biodiversity 2012  , 9, 2618 and references given therein. [2] S. Daum, M. Schumann, S. Mathea, T. Aum�ller, M. A. Balsley, S. L. Constant, B. F�aux de Lacroix, F. Kruska, M. Braun, C. Schiene-Fischer, C., Biochemistry 2009  , 48, 6268. [3] B. A. Nacev, W.-K. Low, Z. Huang, T. T. Su, Z. Su, H. Alkuraya, D. Kasuga, W. Sun, M. Tr�ger, M. B., G. Fischer, K. Zhang, J. O. Liu, J. Pharmacol. Exp. Ther. 2011  , 338, 466.

Aryl indanyl- and aryl hetaryl ketones as novel inhibitors of peptidyl-prolyl-cis/trans-isomerases

248th National Meeting (2014)

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