Synthesis of 5-Nitro-2-furancarbohydrazides and Their cis-Diamminedichloroplatinum Complexes as Bitopic and Irreversible Human Thioredoxin Reductase Inhibitors
2005
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 biligand irreversible inhibitors of the human enzyme with nanomolar affinities. ...
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