5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl–DNA Phosphodiesterase I

Citations Over TimeTop 18% of 2012 papers

Abstract

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

Related Papers

• → Characterization of inhibitors of phosphodiesterase 1C on a human cellular system(2007)36 cited
• → Inhibition of human platelet aggregation by dihydropyrano- and dihydrofuranocoumarins, a new class of cAMP-phosphodiesterase inhibitors(1985)28 cited
• → Effects of saterinone and its enantiomers R(+)-saterinone and S(−)-saterinone on the phosphodiesterase isoenzymes from ventricular tissue of failing human hearts and porcine hearts(1994)13 cited
• → Effect of a cGMP-specific phosphodiesterase inhibitor on retinal function(1998)25 cited
• → The Phosphodiesterases in the Rat Pancreas(1970)6 cited