Studies toward Novel Peptidomimetc Inhibitors of Thioredoxin-Thiredoxin Reductase System

Ryszard Ostaszewski 1,2Szymon Kłossowski 2Angelika Muchowicz 3Jakub Gołąb 3

1. Industrial Chemistry Research Institute (ICRI), Rydygiera 8, Warszawa 01-793, Poland
2. Instytut Chemii Organicznej Polskiej Akademii Nauk (ICHOPAN), Kasprzaka 44/52, Warszawa 01-224, Poland
3. Medical University of Warsaw, Chałubińskiego 5, Warsaw 02-004, Poland


Thioredoxins (Trx) are ubiquitous multifunctional low-molecular weight proteins that together with thioredoxin reductases (TrxR) participate in the maintenance of protein thiol homeostasis in NADPH-dependent reactions. An increasing number of data reveal that the Trx−TrxR system is an attractive target for anticancer therapies. Based on our studies on synthesis on the successful combination of mutlicomponent reactions with enzymatic transformations to the synthesis of bioactive tripeptide mimetics [1,2,3], we have elaborated a new and simple synthetic approach employing Ugi reaction to synthesize several new inhibitors of this system. The influence of various electrophilic fragments of this new class of compounds on the inhibition of the Trx−TrxR system was evaluated. As a result, a new compound SK053, which inhibits the activity of the Trx−TrxR system and exhibits antitumor activity, was obtained. Biologic analyses revealed that SK053 inhibits induction of NF-κB and AP-1 and decreases H2O2 scavenging capacity in tumor cells.

The results of our studies on the successful application of mutlicomponent Ugi reactions to the synthesis of bioactive tripeptide mimetics, will be presented [4].


[1] Szymanski, W., Ostaszewski, R.; Tetrahedron: Asymmetry, 17, 2667-2671, 2006.

[2] Mroczkiewicz M., Ostaszewski R., Tetrahedron, 65, 4025-4034, 2009.

[3] M. Mroczkiewicz, K. Winkler, D. Nowis, G. Placha, J. Golab,R. Ostaszewski, J. Med. Chem., 53, 2010, 1509–1518.

[4] S. Kłossowski , A. Muchowicz, M. Firczuk, M. Świech, A. Redzej, J. Golab, R. Ostaszewski, J. Med Chem. 55, 2012, 55-67.


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Presentation: Oral at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Ryszard Ostaszewski
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-15 14:17
Revised:   2012-03-15 14:17