Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Ribeiro, Carlos J.A.; Kankanala, Jayakanth; Xie, Jiashu; Williams, Jessica; Aihara, Hideki; Wang, Zhengqiang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 2(2019)
• Page Start: 257
• Page End: 261
• Publication Date: 2019-01-15
• Subjects: Tyrosyl-DNA phosphodiesterase 2 (TDP2) -- Anti-cancer -- Triazolo-pyrimidines -- Triazolo-pyridines; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Four derivatives possess significant TDP2 inhibition (IC50 < 50 µM). 17z (IC50 of 21.0 ± 2.1 µM) shows excellent cell permeability and no cytotoxicity. Correct structure of P10A10 was found to be 5-phenyl triazolopyrimidine regioisomer. Abstract: 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 analogue6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer7a . 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, and17z ) with significant TDP2 inhibition (IC50 < 50 µM), with17z showing excellent cell permeability and no cytotoxicity.