文献类型：期刊文献

英文题名：Synthesis and biological properties of maleimide-based macrocyclic lactone enediynes

作者：Li, Xiaoxuan[1];Lu, Haotian[1];Ji, Mingming[1];Sun, Ke[1];Pu, Fangxu[1];Ding, Yun[1];Hu, Aiguo[1]

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

年份：2022

卷号：20

期号：27

起止页码：5481

外文期刊名：ORGANIC & BIOMOLECULAR CHEMISTRY

收录：;EI(收录号：20222812342854);WOS:【SCI-EXPANDED(收录号:WOS:000819501100001)】；

基金：The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (21871080, 21503078, 21474027) and the Shanghai Leading Academic Discipline Project (B502). AH acknowledges the "Eastern Scholar Professorship" support from Shanghai local government and Dr. Junyou Wang for his kind help in cellular experiments.

语种：英文

外文关键词：Atoms - Chemical bonds - Differential scanning calorimetry - Esters - Paramagnetic resonance - Thermodynamic stability

摘要：Natural enediyne antibiotics are powerful DNA-cleavage agents due to the presence of the highly reactive hex-3-ene-1,5-diyne units. However, the complicated chemical structure and thermal instability make their synthesis, derivatization, and storage challenging. Heterocycle-fused enediynes, which exhibit strong antineoplastic activity, are promising analogues of natural enediynes for medicinal applications. To this end, a series of maleimide-based enediynes with macrocyclic lactone moieties were synthesized through the Sonagashira coupling reaction. Differential scanning calorimetry and electron paramagnetic resonance results showed that these macrocyclic enediynes exhibited a rather low onset temperature and the ability to generate radicals at physiological temperature. In addition, the structure-activity relationship of enediynes was analyzed by changing the ring size and the substituents on the propargyl group. Cellular experiments indicated that the diradicals produced by these enediynes efficiently cleaved DNA and disrupted the cell cycle distribution, and consequently induced tumor cell death via an apoptosis pathway at low half inhibitory concentrations. Computational studies suggested that the maleimide moiety promoted the propargyl-allenyl rearrangement of the cyclic enediyne, enabling the generation of diradical species through the Myers-Saito cyclization, and then abstracted hydrogen atoms from the H-donors.