| Autor: |
Saiz, Cecilia, Castillo, Valerie, Fontán, Pablo, Bonilla, Mariana, Salinas, Gustavo, Rodríguez-Haralambides, Alejandra, Mahler, S. |
| Zdroj: |
Molecular Diversity; Feb2014, Vol. 18 Issue 1, p1-12, 12p |
| Abstrakt: |
In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine ( 2af) was identified, upon library analysis by HPLC (IC $$_{50}$$ = 24 $$\upmu $$ M). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure-activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine ( 2aj) as the best enzyme inhibitor in these series, with an IC $$_{50}$$ = 14 $$\upmu $$ M. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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