文献类型：期刊文献

英文题名：Design, synthesis, and biological evaluation of C-10-esterified dihydroartemisinin-cinnamic acid hybrids as anticancer agents against colorectal cancer

作者：Yang, Kaixu[1];Cui, Mengjie[1];Bejoma, Typhaine[1];Lv, Jiagang[1];Li, Along[1];Peng, Xuejing[2];Zhao, Qingjie[1]

第一作者：Yang, Kaixu

通信作者：Zhao, QJ[1];Peng, XJ[2]

机构：[1]Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, State Key Lab Discovery & Utilizat Funct Component, Shanghai 201203, Peoples R China;[2]Gansu Univ Chinese Med, Lanzhou 730000, Peoples R China

第一机构：Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, State Key Lab Discovery & Utilizat Funct Component, Shanghai 201203, Peoples R China

通信机构：[1]corresponding author), Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, State Key Lab Discovery & Utilizat Funct Component, Shanghai 201203, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：317

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001811468600001)】；

基金：This work was supported by the Initial Funding for Distinguished Scholars of Shanghai University of Traditional Chinese Medicine (A1-U24-205-020404) .

语种：英文

外文关键词：Dihydroartemisinin; Cinnamic acid; Stereoselective synthesis; Colorectal cancer; Hybrid

摘要：Dihydroartemisinin (DHA) attracts considerable attention as a promising antineoplastic agent against colorectal cancer. However, its suboptimal antitumor efficacy and its C-10 configurational lability driven by hemiacetalmediated epimerization collectively impede its clinical development. In this context, a library of 52 DHAcinnamic acid (DHA-CA) hybrid derivatives with defined C-10 stereochemistry was constructed via stereocomplementary esterification: Mitsunobu conditions selectively afforded 10(1-configured esters, whereas HATUmediated acylation preferentially furnished 10 alpha-isomers. Structure-activity relationship (SAR) exploration revealed that structural modifications, including double-bond saturation, the introduction of electronwithdrawing groups, or altered phenyl substitution patterns, substantially attenuated antiproliferative activity. These findings established that a 10(1-configured CA (alpha,(1-unsaturated ester linkage) combined with a bulky, electron-donating meta-substituent (e.g., tBu) constituted the optimal pharmacophore. Guided by this SAR framework, compound 12b-meta was identified as the most potent derivative against colorectal cancer cell lines, exhibiting IC50 values of 0.057 +/- 0.014 mu M (HT-29) and 0.067 +/- 0.016 mu M (HCT 116), with a selectivity index (SI) exceeding 447 against NCM460 normal colon mucosal epithelial cells. This profile represents a 52- and 86fold enhancement in potency relative to DHA. Mechanistic studies showed that 12b-meta suppressed colony formation and DNA synthesis, induced G0/G1 arrest, and was accompanied by reduced Cyclin D1/CDK4 expression. Quantitative proteomic profiling revealed downregulation of proteins related to DNA replication and mitochondrial translation, and immunoblot analysis confirmed RRM2 downregulation. Moreover, 12b-meta showed moderate human plasma stability, with 53.4% remaining after 240 min. These findings established the meta-tBu CA-DHA scaffold as a platform for a potential preclinical optimization in colorectal cancer drug discovery.