Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547.2 Organic chemical reactions formerly 547.139
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: p. 257-261 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260126
• Chủ đề: 1. 60 applied life sciences; 2. Anti-cancer; 3. Triazolo-pyridines; 4. Triazolo-pyrimidines; 5. Tyrosyl-dna phosphodiesterase 2 (tdp2)

Tóm tắt

 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 (IC<
 sub>
 50<
 /sub>
  <
  50 ?M), with 17z showing excellent cell permeability and no cytotoxicity.