马来酰亚胺基烯二炔化合物对生物大分子的损伤作用  

Cleavage of Biological Macromolecules by Maleimide-Based Enediyne Compounds

作　　者：孙可 鲁浩天 张梦思 胡爱国[1] SUN Ke;LU Haotian;ZHANG Mengsi;HU Aiguo(Shanghai Key Laboratory of Advanced Polymeric Materials,School of Materials Science and Engineering,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]华东理工大学材料科学与工程学院,上海市先进聚合物材料重点实验室,上海200237

出　　处：《华东理工大学学报（自然科学版）》2023年第5期615-622,共8页Journal of East China University of Science and Technology

基　　金：国家自然科学基金(21871080)。

摘　　要：利用Sonogashira偶联反应合成了3种具有不同羟基数量的马来酰亚胺基烯二炔,它们可以通过马来酰亚胺促进的重排和环芳香化反应(MARACA)作用机制产生高活性的双自由基中间体。电子顺磁共振实验结果证实了体系中自由基中间体的产生。DNA凝胶电泳实验结果证实了这些烯二炔能够在生理温度下对质粒DNA产生裂解作用,并表现出浓度依赖性。蛋白质凝胶电泳实验结果表明烯二炔对蛋白质的降解能力与其产生自由基的能力一致。对于炔丙位上具有杂原子的高反应活性烯二炔,其可在低浓度(5 mmol/L)下破坏蛋白质主链结构的完整性致使蛋白质失活。研究结果为探究马来酰亚胺基烯二炔分子对病毒蛋白质等生物大分子的损伤作用奠定了基础,为开发此类分子潜在的临床应用价值提供了新的思路。Three maleimide-based enediynes with different numbers of hydroxyl groups at the alkyne ends were synthesized by Sonogashira coupling reaction between diiodomaleimide and different terminal alkynes.Through the maleimide assisted rearrangement and cycloaromatization(MARACA)mechanism,these enediyne molecules were converted to enyne-allenes at room temperature,producing highly reactive diradical intermediates through Myer-Saito cyclization reactions.Electron paramagnetic resonance confirmed the generation of free radical intermediates in the system by using the free radical trapping agent,N-tert-Butyl-α-phenylnitrone.DNA gel electrophoresis indicated that these enediynes generated highly reactive free radicals,which further deprived hydrogen atoms from the DNA backbone at physiological temperature,resulting in the fragmentation of plasmid DNA strands and cleavage of supercoiled DNA into the cyclic form.The DNA cleavage process is concentration-dependent,and different enediyne structures exhibited different cleaving effects over the same concentration gradient.Protein gel electrophoresis showed that the ability of the enediyne compounds to degrade proteins agreed with that to produce free radicals.In the presence of a highly reactive enediyne with an oxygen atom at the propargyl position,the structural integrity of the protein backbone was destroyed at a low concentration(5 mmol/L)of enediyne compounds,resulting in protein denaturing.Taken together,this work provides an insight into exploiting maleimide-based enediyne for the structural degradation of a variety of biological macromolecules such as proteins and oncogenes.

关 键 词：烯二炔 MARACA反应 双自由基 DNA 蛋白质 

分 类 号：O621.3[理学—有机化学]