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

Sameera Senaweera, Tianyu He, Haixi Cui, Hideki Aihara, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review


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 analogs (subtype 11), or any other C-4 modifications (subtypes 13-15) except for the benzylidene substitution (subtype 12), where eight analogs showed low micromolar potency. The best analog, 12q, inhibited TDP2 with an IC50 of 4.8 μM. Molecular modeling was performed to help understand the observed SAR trends. Overall, these SAR observations which could significantly benefit future work on the design of improved TDP2 inhibitors. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)371-386
Number of pages16
JournalMedicinal Chemistry Research
Issue number2
StatePublished - Feb 2021

Bibliographical note

Funding Information:
This research was supported by the University of Minnesota AHC Faculty Research Development Grant (to ZW and HA), and the National Institutes of Health grant GM118047 (to HA). We thank the Center for Drug Design, University of Minnesota for the support, and the Minnesota Supercomputing Institute (Minneapolis, USA) for molecular modeling resources.


  • 3(2H
  • 4H)-dione
  • Anti-cancer
  • Tyrosyl-DNA phosphodiesterase 2 (TDP2)
  • benzylideneisoquinoline-1

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