Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide

Jayakanth Kankanala, Carlos J.A. Ribeiro, Evgeny Kiselev, Azhar Ravji, Jessica Williams, Jiashu Xie, Hideki Aihara, Yves Pommier, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.

Original languageEnglish (US)
Pages (from-to)4669-4682
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
DOIs
StatePublished - May 9 2019

Bibliographical note

Funding Information:
This research was supported by the Academic Health Center Faculty Research Development Grant Program (FRD #14.23), University of Minnesota (to HA and ZW), and in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute (Z01 BC 006161-17) and NIGMS R35 GM118047 (to HA). We acknowledge Professor Bert Semler at University of California, Irvine and Professor Haitao Guo at Indiana University School of Medicine, for providing HeLa and HepG2 Cells, respectively, and the Minnesota Supercomputing Institute (MSI) for computational resources.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

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