jm5b01284_si_001.pdf (7.17 MB)
Synthesis and Mechanism Studies of 1,3-Benzoazolyl Substituted Pyrrolo[2,3‑b]pyrazine Derivatives as Nonintercalative Topoisomerase II Catalytic Inhibitors
journal contribution
posted on 2016-01-14, 00:00 authored by Peng-Hui Li, Ping Zeng, Shuo-Bin Chen, Pei-Fen Yao, Yan-Wen Mai, Jia-Heng Tan, Tian-Miao Ou, Shi-Liang Huang, Ding Li, Lian-Quan Gu, Zhi-Shu HuangNovel topoisomerase II (Topo II)
inhibitors have gained considerable
interest for the development of anticancer agents. In this study,
a series of 1,3-benzoazolyl-substituted pyrrolo[2,3-b]pyrazine derivatives were designed, synthesized, and evaluated as
potential Topo II catalytic inhibitors. It was found that some of
derivatives had good antiproliferative activity on seven cancer cell
lines, especially on HL-60/MX2, a cancer cell line derivative from
HL-60 that is resistant to Topo II poison. Topo II mediated DNA relaxation
assay results showed that derivatives could significantly inhibit
the activity of Topo II, and the structure–activity relationship
studies indicated the importance of the alkylamino side chain and
the benzoazolyl group. Further mechanism studies revealed that derivatives
function as Topo II nonintercalative catalytic inhibitors and may
block the ATP binding site of Topo II. Moreover, flow cytometric analysis
showed that this class of compounds could induce apoptosis of HL-60
cells.