文献类型：期刊文献

英文题名：Synthesis of maleimide-based enediynes with cyclopropane moieties for enhanced cytotoxicity under normoxic and hypoxic conditions

作者：Wang, Wenbo[1];Lu, Haotian[1];Zhang, Mengsi[1];Ma, Hailong[1];Cheng, Xiaoyu[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：2021

卷号：9

期号：22

起止页码：4502

外文期刊名：JOURNAL OF MATERIALS CHEMISTRY B

收录：;EI(收录号：20212410504980);WOS:【SCI-EXPANDED(收录号:WOS:000652687600001)】；

基金：Dedicated to the 100th anniversary of Chemistry at Nankai University. The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (21871080, 21503078, 21474027), the Fundamental Research Funds for the Central Universities (22221818014), and the Shanghai Leading Academic Discipline Project (B502). AH acknowledges the "Eastern Scholar Professorship'' support from Shanghai local government.

语种：英文

外文关键词：Atoms - Tumors - Cell death - DNA - Propane - Binding energy - Reaction intermediates

摘要：Myers-Saito cycloaromatization (MSC) is the working mechanism of many natural enediyne antibiotics with high antitumor potency. However, the presence of the equilibrium between diradical and zwitterionic intermediates in MSC severely hinders further improvement in cytotoxicity toward tumor cells. To this end, a series of maleimide-based enediynes with cyclopropane moieties were synthesized for enhanced cytotoxicity toward tumor cells. By taking advantage of radical clock reactions, the diradical intermediates generated from MSC would rearrange to new diradicals with much longer separation and weaker interactions between two radical centers. The computational study suggested a low energy barrier (4.4 kcal mol(-1)) for the radical rearrangement through the cyclopropane ring-opening process. Thermolysis experiments confirmed that this radical rearrangement results in the formation of a new diradical intermediate, followed by abstracting hydrogen atoms from 1,4-cyclohexadiene. Interestingly, the DNA cleavage ability and cytotoxicity of enediynes were significantly enhanced after the introduction of cyclopropane moieties. In addition, these maleimide-based enediynes exhibited a similar cytotoxicity under hypoxic conditions to that under normoxic conditions, which is beneficial for treating solid tumors where hypoxic environments frequently lead to deteriorated efficiency of many antitumor drugs. Docking studies indicated that the diradical intermediate was located between the minor groove of DNA with a binding energy of -7.40 kcal mol(-1), which is in favor of intracellular DNA damage, and thereby inducing cell death via an apoptosis pathway as suggested by immunofluorescence analysis.