Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Shijingshan District, Beijing 100049, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Shijingshan District, Beijing 100049, China.
Bioorg Med Chem. 2021 Dec 1;51:116497. doi: 10.1016/j.bmc.2021.116497. Epub 2021 Nov 10.
Antibody-drug conjugates (ADCs) have emerging as efficient agents to target deliver cytotoxic drugs and reduce their off-target side effects. Triptolide has attracted attention to be used in ADC development. Herein, three rationally designed triptolide drug-linkers have been synthesized for use in site-specific construction of ADCs. Carbamates that were supposed to be more stable than carbonates were introduced to attach triptolide to the linkers. PEG and discrete PEG chains were incorporated to improve the hydrophilicity of drug-linkers. The ADCs were finally site-specifically prepared by conjugation of the drug-linkers to trastuzumab through disulfide re-bridging approach. The preliminary anti-tumor activities of these ADCs were evaluated and they displayed high potencies against HER2-targeted cancer in vitro and in vivo.
抗体药物偶联物 (ADC) 作为一种高效的靶向药物，能够将细胞毒性药物递送至靶部位，并降低其脱靶副作用。雷公藤红素已被用于 ADC 开发，受到广泛关注。本文设计并合成了三种雷公藤红素连接子，用于 ADC 的定点构建。引入了比碳酸酯更稳定的氨基甲酸酯，以将雷公藤红素连接到连接子上。引入聚乙二醇 (PEG) 和离散的 PEG 链，以提高药物连接子的亲水性。最后通过二硫键重新桥接的方法，将药物连接子定点连接到曲妥珠单抗上，制备 ADC。对这些 ADC 的初步抗肿瘤活性进行了评估，它们在体外和体内对 HER2 靶向癌症表现出高活性。
