天冬酰胺类抗体-药物偶联物连接子的合成新工艺  

A novel synthetic technology of asparagine antibody-drug conjugate linker

作　　者：林子健 曹小冬 LIN Zijian;CAO Xiaodong(School of Science,Zhejiang Sci-Tech University,Hangzhou 310018,China)

机构地区：[1]浙江理工大学理学院,杭州310018

出　　处：《浙江理工大学学报（自然科学版）》2023年第5期612-617,共6页Journal of Zhejiang Sci-Tech University(Natural Sciences)

摘　　要：为了提高抗体-药物偶联物(Antibody-drug conjugate,ADC)的连接子4-N-(N-(L-丙氨酰-L-丙氨酰)-N′-三苯甲基-L-天冬酰胺酰基)-氨基苯甲醇(NH_(2)-AAN(Trt)-PAB)的合成效率,设计了一条新的合成路线。以N-芴甲氧羰基-N′-三苯甲基-L-天冬酰胺为起始原料,经过氨基酸缩合、氨基脱保护4步反应,高效合成了NH_(2)-AAN(Trt)-PAB。LCMS、1H NMR分析表征结果表明成功合成了NH_(2)-AAN(Trt)-PAB。该研究具有操作简便、条件温和可控、合成效率高、总产率较高等特点,有利于NH_(2)-AAN(Trt)-PAB的放大生产及其在ADC药物研发中的应用,同时对其他蛋白酶可裂解连接子的合成具有借鉴意义。To improve the synthesis efficiency of the linker NH_(2)-AAN(Trt)-PAB of antibody-drug conjugate(ADC),we designed a new synthetic route.With Fmoc-Asn(Trt)-OH as the raw material,NH_(2)-AAN(Trt)-PAB was efficiently synthesized through four steps including amino acid condensation and amino deprotection.The results of LCMS and~1H NMR analysis indicate the successful synthesis of NH_(2)-AAN(Trt)-PAB.This synthesis route has many advantages,such as simple operation,mild condition,high efficiency,and high yield,which is conducive to the scale-up production of NH_(2)-AAN(Trt)-PAB and its application in ADC drug research and development.It has reference significance for the synthesis of other protease cleavable linkers.

关 键 词：抗体-药物偶联物 连接子 天冬酰胺 氨基酸缩合 氨基脱保护 可裂解连接子 

分 类 号：O622.6[理学—有机化学]