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.

Acknowledgment:

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

References:
[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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