Synthesis of novel, thioredoxin - thioredoxin reductase inhibitors

Adam Redzej 1Ryszard Ostaszewski 1Andżelika Szokalska 2Jakub Gołąb 2

1. Polish Academy of Science, Institute of Organic Chemistry, Kasprzaka 44/52, Warszawa 01-224, Poland
2. Medical University of Warsaw (AM), Banacha 1, Warszawa 02-097, Poland


Thioredoxin-1 (Trx-1) is a protein which is over-expressed in many human tumors. The increased level of this protein in cells results in aggressive tumor growth and decreased patient survival.

Because of its role in promoting cell survival, proliferation and tumor angiogenesis, Trx-1 is an attractive molecular target. Therefore many studies have been done in order to obtain a selective inhibitor of Trx-1. One of such compounds is 2-[(1-Methylpropyl)dithio]-1H-imidazole (PX-12) (1). It is a small molecule which causes the oxidation of cysteine residues both in thioredoxin reductase (TR) and thioredoxin. But it irreversibly inhibits only Trx-1. [1] The second inhibitor of TR-Trx system is b,b-dibromoisobutyric acid methyl ester(2). [2]

Although biological activity of these two compounds is well described in literature, still not much is known about the mechanism of inhibition.

We will present the results of our studies on the synthesis of peptidomimetics possessing
b,b-dihalogeno-iso-butyric group (3) and on the influence of main structural features of studied compounds, such as leaving group (X=Cl, Br, I, Ms, Trf) and substituents (R1, R2) on biological activity.


Supported by a grant from the Ministry of Science and Higher Education no. N N405 3202 33

[1] Kelly Huber, Poulam Patel, Lei Zhang, Helen Evans, Andrew D. Westwell, Peter M.
Fischer, Stephen Chan and Stewart Martin, Mol Cancer Ther 2008, 7, 143

[2] US Patent 5712417


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Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Adam Redzej
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-03-14 10:16
Revised:   2009-06-07 00:48