title: 5-Arylidenethioxothiazolidinones as inhibitors of tyrosyl-DNA phosphodiesterase I.
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.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Sirivolu
authors.forename: Sanjeev Kumar V
authors.initials: SK
authors.lastname: Vernekar
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Alena
authors.initials: A
authors.lastname: Naumova
authors.forename: Adel
authors.initials: A
authors.lastname: Chergui
authors.forename: Amelie
authors.initials: A
authors.lastname: Renaud
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Stephen
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D002645:Chickens; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010726:Phosphodiesterase Inhibitors; D053778:Thiazolidines; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human