文献类型：期刊文献

英文题名：Triggering the Antitumor Activity of Acyclic Enediyne through Maleimide-Assisted Rearrangement and Cycloaromatization

作者：Zhang, Mengsi[1];Li, Baojun[1];Chen, Huimin[1];Lu, Haotian[1];Ma, Hailong[1];Cheng, Xiaoyu[1];Wang, Wenbo[1];Wang, Yue[1];Ding, Yun[1];Hu, Aiguo[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab Adv Polymer Mat, Sch Mat Sci & Engn, Shanghai 200237, Peoples R China

年份：2020

卷号：85

期号：15

起止页码：9808

外文期刊名：JOURNAL OF ORGANIC CHEMISTRY

收录：;EI(收录号：20203609124367);WOS:【SCI-EXPANDED(收录号:WOS:000562073600032)】；

基金：The authors gratefully acknowledge the financial support from National Natural Science Foundation of China (21871080, 21503078), the Fundamental Research Funds for the Central Universities (22221818014), and Shanghai Leading Academic Discipline Project (B502). A.H. thanks the "Eastern Scholar Professorship" support from Shanghai local government. A.H. thanks Profs. Runhui Liu and Junyou Wang for their kind help in cellular experiments.

语种：英文

外文关键词：Cyclization - Physiology

摘要：Acyclic enediynes are generally inactive under physiological conditions to be used as antitumor agents like their natural enediyne counterparts. A new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) is uncovered to trigger the reactivity of acyclic enediynes. Through this mechanism, cascade 1,3-proton transfer processes are accelerated with the maleimide moiety at the ene position to enable the acyclic enediynes to undergo cycloaromatization and generate reactive radicals under physiological conditions. Computational studies suggest that the highest energy barrier for MARACA is 26.0 kcal/mol, much lower than that of Bergman cyclization pathway (39.6 kcal/mol). Experimental results show that maleimide-based enediynes exhibit low onset temperature, fast generation of radical species at 37 degrees C, and much faster reaction in aqueous solution than in nonpolar solvent, which is beneficial to achieve both high reactivity in physiological environment and high stability for storage and delivery in nonpolar media. The generated radical species are capable of causing high percentage of double-strand (ds) DNA cleavage, leading to significant cytotoxicity toward a panel of cancer cell lines with half inhibition concentration down to submicromolar level. Overall, the discovery of the MARACA mechanism provides a platform for designing novel acyclic enediynes with high potency for antitumor applications.