Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

Ribeiro, Carlos J. A.; Kankanala, Jayakanth; Xie, Jiashu; Williams, Jessica; Aihara, Hideki; Wang, Zhengqiang

doi:10.1016/j.bmcl.2018.11.044

Title: Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

Journal Article · Thu Nov 22 00:00:00 EST 2018 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2018.11.044· OSTI ID:1502193

Ribeiro, Carlos J. A. ^[1]; Kankanala, Jayakanth ^[1]; Xie, Jiashu ^[1]; Williams, Jessica ^[1]; Aihara, Hideki ^[1];

^[1]

Univ. of Minnesota, Minneapolis, MN (United States)

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. In this artilce, we report that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC₅₀ < 50 μM), with 17z showing excellent cell permeability and no cytotoxicity.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Academic Health Center Faculty Research Development Grant Program; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: GM118047; 1224900

OSTI ID:: 1502193

Journal Information:: Bioorganic and Medicinal Chemistry Letters, Vol. 29, Issue 2; ISSN 0960-894X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 15 works

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60 APPLIED LIFE SCIENCES
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Title: Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors

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