含咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物的合成及抗急性髓系白血病活性研究

doi:10.6023/cjoc202403053

摘要/Abstract

本文合成了一系列含有咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物,评估了这些化合物对FLT3-ITD激酶的抑制作用和对表达FLT3-ITD的两种急性髓系白血病细胞株的抗增殖作用。基于咪唑并[1,2-a]吡啶的不同取代基,对22种化合物进行了初步的构效关系探索。结果表明,化合物11e-11h、11j、12a-12c对FLT3-ITD激酶具有一定的抑制作用,IC₅₀值均低于0.5 µM。其中,化合物12a具有最佳的FLT3-ITD激酶抑制活性,且对表达FLT3-ITD的细胞系MV4-11和MOLM-13抗增殖作用最强,IC₅₀值分别为0.06 µM和0.2 µM。此外,12a对非FLT3突变的细胞系无抗增殖作用,如THP-1、HCT-116、A549、HepG2、K562和MCF-7细胞,且对正常HK-2（人肾小管上皮细胞）、HepaRG（人肝祖细胞）和HEK293（人胚胎肾细胞）无细胞毒性。本研究中发现的化合物12a,虽然其对FLT3-ITD激酶的抑制活性和抗肿瘤细胞增值活性弱于阳性药Cabozantinib,但可为FLT3-ITD抑制剂的进一步研究提供一定的参考。

关键词: 咪唑并[1,2-a]吡啶, 抗增殖活性, 抑制作用, FLT3激酶, 急性髓系白血病

A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized in this work. The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated. Focused on the different substitutions of imidazo[1,2-a]pyridine, a preliminary exploration of the structure-activity relationship was conducted for 22 compounds. The results revealed that compounds 11e-11h, 11j, and 12a-12c exhibited certain inhibitory effects on FLT3-ITD kinase, with IC₅₀ values below 0.5 µM. Among them, compound 12a demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD, with IC₅₀ values of 0.06 µM and 0.2 µM, respectively. Moreover, compound 12a didnot exhibit anti-proliferative activity against cell lines without FLT3 mutations, such as THP-1, HCT-116, A549, HepG2, K562, and MCF-7, and it displayed non-cytotoxicity towards normal HK-2 (human renal tubular epithelial cells), HepaRG (human liver progenitor cells), and HEK293 (human embryonic kidney cells). Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to Cabozantinib in this study, it can provide a reference for further research into FLT3-ITD inhibitors.

Key words: Imidazole[1,2-a]pyridine, Antiproliferative activity, Inhibition, FLT3 kinase, Acute myeloid leukemia

引用此文

吴律嘉, 黎江东, 石忠花, 金鑫, 王先恒, 赵长阔, 黄强. 含咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物的合成及抗急性髓系白血病活性研究[J]. 有机化学, doi: 10.6023/cjoc202403053.

Lvjia Wu, Jiangdong Li, Zhonghua Shi, Xin Jin, Xianheng Wang, Changkuo Zhao, Qiang Huang. Synthesis and Anti-acute Myeloid Leukemia Activity of Cyclopropane-1,1-diamide Derivatives Containing Imidazo[1,2-a]pyridine[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202403053.

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