Small Molecules to Target the Selenoprotein Thioredoxin Reductase

Abstract

The selenoprotein thioredoxin reductase (TrxR) enzymes are the only identified proteins that maintain thioredoxin (Trx) proteins in a reduced state under physiological conditions, and consequently play a pivotal role in the regulation of various cellular redox signaling pathways involved in cell differentiation, growth, and death. The elevated expression of TrxR enzymes has been observed in different types of cancer cells, and this overexpression is of pathological significance in maintaining tumor phenotypes, such as uncontrolled proliferation and resistance to apoptosis. Herein, we discuss recent advances in the study of TrxR, including classic assays of TrxR, the emerging chemical tools of TrxR, and small molecules that target TrxR as potential anticancer agents.

Natural‐Like Spirocyclic Δα,β‐Butenolides Obtained from Diazo Homophthalimides

“…[23][24][25] TrxR is a selenocystein enzyme, one of only a few dozen encoded in the human genome [26] and the selective targeting of the selenocysteine residue by electrophilic compounds (specifically, Michael acceptors) -in the presence of much more abundant nucleophilic cysteines -has been regarded as the key to achieving therapeutic success. [27] With 23 novel Δ α,β -spirobutenolides at hand (4 a-o and 7 ah), we became curious if this new chemotype would be, on the one hand, capable of inhibiting TrxR and, on the other hand would display potential for selective targeting of selenocysteine in the chemically reconstituted excess-cysteine environment.…”

Fluorescent probes based on nucleophilic aromatic substitution reactions for reactive sulfur and selenium species: Recent progress, applications, and design strategies

“…RSS- and RSeS-specific fluorescent probes have long been used for protein labeling [37] , [66] , [67] , [68] . For the purpose of drug simulation and structural screening, researchers have synthesized various RSS-specific fluorescent probes [69] .…”

“…At the beginning of the 21st century, researchers synthesized various types of highly selective RSeS-specific fluorescent probes capable of operating under physiological conditions by simulating the structure of RSS probes and optimizing the detection environment. Fluorescent probes based on S N Ar reaction for RSS and RSeS have been hot spots in this field [7] , [8] , [66] .…”

Cyclic 5-Membered Disulfides Are Not Selective Substrates of Thioredoxin Reductase, but Are Opened Nonspecifically by Thiols

“…30,31 In contrast however, 1,2-dithiolanes have also been reported as reduction-sensing units with a remarkable selectivity for TrxR. The fluorogenic TRFS probes 14,16,32,33 and prodrugs 15 have been commercialised and extensively reviewed [34][35][36][37][38] (Fig 1e; overview in Fig S1b). These probes have since been used to study the role of TrxR in Parkinson's disease 39 and stroke 33 , and have been employed for mechanistic validation of putative TrxR inhibitors during screening approaches.…”