TY - JOUR
T1 - Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors
AU - Ribeiro, Carlos J.A.
AU - Kankanala, Jayakanth
AU - Xie, Jiashu
AU - Williams, Jessica
AU - Aihara, Hideki
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/1/15
Y1 - 2019/1/15
N2 - 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. 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 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 (IC 50 < 50 µM), with 17z showing excellent cell permeability and no cytotoxicity.
AB - 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. 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 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 (IC 50 < 50 µM), with 17z showing excellent cell permeability and no cytotoxicity.
KW - Anti-cancer
KW - Triazolo-pyridines
KW - Triazolo-pyrimidines
KW - Tyrosyl-DNA phosphodiesterase 2 (TDP2)
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U2 - 10.1016/j.bmcl.2018.11.044
DO - 10.1016/j.bmcl.2018.11.044
M3 - Article
C2 - 30522956
AN - SCOPUS:85057777745
SN - 0960-894X
VL - 29
SP - 257
EP - 261
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 2
ER -