Natural-like scaffolds targeting thioredoxin reductase for anticancer therapy

Abstract

Selenoprotein thioredoxin reductase (TrxR) is known to have several different roles in relation to cancer. Many studies have suggested that the whole thioredoxin (Trx) system (driven by NADPH comprising TrxR/Trx) is important in carcinogenesis and in cancer progression, making it promising therapeutic target. Due to its inherent chemical reactivity, TrxR might be easily inhibited by a wide range of small natural-like compounds. Typically, TrxR is inhibited by electrophiles (Michael acceptors) through the targeting of its reactive selenocysteine residue. Another type of recently described approach comprises the use of acyclic/cyclic disulfides, which can be selectively reduced by TrxR in cells. These redox-sensitive molecules can operate along diverse pathways via a thiol–disulfide mechanism in which disulfide bonds are reversibly formed and reduced, thus switching the molecules between different functional states. As part of our interests in discovering and developing small molecules targeting the TrxR/Trx system, herein we report synthesis, and biological evaluation of 3,4-di-unsubstituted coumarins 1 and 1,2-dithiolanes 2 derivatives. A small library of derivatized coumarins and 1,2-dithiolane analogues has been obtained and tested for its TrxR inhibition activity with promising preliminary biological results. It is also important to emphasize that utilization of scaffolds of natural products is beneficial because low or no toxicity is expected.