Synthesis of 5-nitro-2-furancarbohydrazides and their cis-diamminedichloroplatinum complexes as bitopic and irreversible human thioredoxin reductase inhibitors
| Autor: | Sabine Urig, Eberhard Amtmann, Judit Jacob, Stephan Gromer, Jacques-Philippe Moulinoux, Katja Becker, Elisabeth Davioud-Charvet, Régis Millet |
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| Rok vydání: | 2005 |
| Předmět: |
Thioredoxin-Disulfide Reductase
Time Factors Organoplatinum Compounds Stereochemistry Thioredoxin reductase Antineoplastic Agents Reductase chemistry.chemical_compound Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Animals Humans Furans Cisplatin chemistry.chemical_classification biology Selenocysteine Nitroreductases Kinetics Enzyme Drosophila melanogaster Hydrazines chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Selenoprotein Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 48(22) |
| ISSN: | 0022-2623 |
| Popis: | The human selenoprotein thioredoxin reductase is involved in antioxidant defense and DNA synthesis. As increased thioredoxin reductase levels are associated with drug sensitivity to cisplatin and drug resistance in tumor cells, this enzyme represents a promising target for the development of cytostatic agents. To optimize the potential of the widely used cisplatin to inhibit the human thioredoxin reductase and therefore to overcome cisplatin resistance, we developed and synthesized four cis-diamminedichloroplatinum complexes of the lead 5-nitro-2-furancarbohydrazide 8 selected from high-throughput screening. Detailed kinetics revealed that the isolated fragments, 5-nitro-2-furancarbohydrazide and cisplatin itself, bind with micromolar affinities at two different subsites of the human enzyme. By tethering both fragments four nitrofuran-based cis-diamminedichloroplatinum complexes 13a-c and 20 were synthesized and identified as bi-ligand irreversible inhibitors of the human enzyme with nanomolar affinities. Studies with mutant enzymes clearly demonstrate the penultimate selenocysteine residue as the prime target of the synthesized cis-diamminedichloroplatinum complexes. |
| Databáze: | OpenAIRE |
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