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

doi:10.1021/acs.jmedchem.9b00274

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 journal › Article › peer-review

18 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 language	English (US)
Pages (from-to)	4669-4682
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00274
State	Published - 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.1021/acs.jmedchem.9b00274

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Kankanala, J., Ribeiro, C. J. A., Kiselev, E., Ravji, A., Williams, J., Xie, J., Aihara, H., Pommier, Y., & Wang, Z. (2019). Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. Journal of Medicinal Chemistry, 62(9), 4669-4682. https://doi.org/10.1021/acs.jmedchem.9b00274

Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. / Kankanala, Jayakanth; Ribeiro, Carlos J.A.; Kiselev, Evgeny et al.
In: Journal of Medicinal Chemistry, Vol. 62, No. 9, 09.05.2019, p. 4669-4682.

Research output: Contribution to journal › Article › peer-review

Kankanala, J, Ribeiro, CJA, Kiselev, E, Ravji, A, Williams, J , Xie, J , Aihara, H, Pommier, Y & Wang, Z 2019, 'Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide', Journal of Medicinal Chemistry, vol. 62, no. 9, pp. 4669-4682. https://doi.org/10.1021/acs.jmedchem.9b00274

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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.",

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N2 - 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.

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

Abstract

Bibliographical note

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