4-Benzylideneisoquinoline-1,3(2H,4H)-diones as tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors.

ABSTRACT: Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (Top2) mediated DNA damages, including double-strand breaks (DSBs) that underpin the anticancer mechanism of clinical TOP2 poisons such as etoposide (ETP). Inhibition of TDP2 could sensitize cancer cells toward TOP2 poisons by increasing Top2 cleavage complex. We have previously identified isoquinoline-1,3-dione as a selective inhibitor type of TDP2. However, the reported structure-activity relationship (SAR) was limited to simple substitutions on the isoquinoline-1,3-dione core. Herein, we report the extended SAR consisting of the synthesis and testing of a total of 50 analogs featuring N-2 and C-4 modifications. Major SAR observations include the loss of potency upon N-2 substitution, the lack of inhibition with C-4 enamine

SUBMITTER: Senaweera S 

PROVIDER: S-EPMC7993140 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature