文献类型：期刊文献

英文题名：Pyridazinedione-Fused Enediyne Antitumor Antibiotics

作者：Zhang, Houjun[1]; Li, Xuejie[2]; Cheng, Haonan[1]; Pu, Fangxu[1]; Zheng, Hongyu[1]; Huang, Xiaohua[1]; Ding, Yun[1]; Lan, Jiaming[2]; Hu, Aiguo[1]

机构：[1] Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China; [2] Chinese Academy of Sciences [CAS] Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China

年份：2024

外文期刊名：SSRN

收录：EI(收录号：20240233495)

语种：英文

外文关键词：Atoms - Cell death - Density functional theory - Differential scanning calorimetry - DNA - Paramagnetic resonance - Physiology

摘要：Natural enediyne antibiotics undergo thermally induced cycloaromatization under physiological conditions to generate highly reactive diradicals, effectively abstract hydrogen atoms from biomacromolecules like DNA, leading to DNA cleavage and inducing programmed cell death in tumor cells, exhibiting potent cytotoxicity and broad-spectrum antitumor properties. In order to further explore promising synthetic analogues of natural enediynes, a 3,6-pyridazinedione moiety was fused at the ene-position, and 10 new enediyne compounds with different atoms at the propargylic positions was synthesized. Differential scanning calorimetry and electron paramagnetic resonance results indicated that these enediynes exhibited a rather low onset temperature and the capability to generate radical species at physiological temperatures. Density Functional Theory calculations demonstrated that the pyridazinedione moiety facilitates cascade rearrangement processes, thereby endowing the key cycloaromatization with a low energy barrier. The enediynes with propargylic oxygen exhibit strong DNA cleavage capabilities, and all pyridazinedione-fused enediynes showed IC50 values in the range of several tens of micromolars against Hela cells. ? 2024, The Authors. All rights reserved.