5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl-DNA Phosphodiesterase i

摘要: Tyrosyl–DNA phosphodiesterase I (Tdp1) is a cellular enzyme that repairs the irreversible topoisomerase (Top1)–DNA complexes and confers chemotherapeutic resistance to Top1 inhibitors. Inhibiting Tdp1 provides an attractive approach potentiating clinically used However, despite recent efforts in studying as therapeutic target, its inhibition remains poorly understood largely underexplored. We describe herein discovery of arylidene thioxothiazolidinone scaffold for potent inhibitors based on initial tyrphostin lead compound 8. Through structure–activity relationship (SAR) studies we demonstrated thioxothiazolidinones inhibit identified 50 submicromolar inhibitor (IC50 = 0.87 μM). Molecular modeling provided insight into key interactions essential observed activities. Some derivatives were also active against endogenous whole cell extracts. These findings contribute advancing understanding T...