Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors
Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors
复制标题
作为有效的自分泌运动素变构抑制剂的新型咪唑并[1,2-a]吡啶衍生物的设计、合成和有前景的抗肿瘤功效
DOI：
10.1016/j.ejmech.2022.114307
复制
发表时间：
2022
影响因子：
6.7
通讯作者：
Xin Zhai
中科院分区：
文献类型：
--
作者：
Hongrui Lei;Xinyu Wang;Guolong Zhao;Tong Li;Youbao Cui;Huinan Wu;Jing Yang;Nan Jiang;Xin Zhai
Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound10cbearing aN-hydroxyethyl piperazinyl group was identified as the optimal ATX inhibitor with an IC50value of 3.4 nM10cexerted the most impressive antitumor effects, especially on Hep3B (0.58 μM) and RAW264.7 (0.63 μM) cell lines highly expressing ATX mRNA. Moreover,10ccould dose-dependently suppress the RAW264.7 cell migration rate in wound healing assay and significantly inhibit RAW264.7 cell colony formation. Meanwhile,10cwas capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together,10cmay serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases.
