连接器
化学
烯二炔
结合
组合化学
抗体-药物偶联物
体外
部分
天然产物
药品
细胞毒性
药理学
计算生物学
抗体
单克隆抗体
立体化学
生物化学
计算机科学
数学分析
操作系统
免疫学
生物
医学
数学
作者
K. C. Nicolaou,Ruofan Li,Qi-Feng Chen,Zhaoyong Lu,Emmanuel N. Pitsinos,Alexander Schammel,Baiwei Lin,Christine Gu,Hetal Sarvaiya,Robert Tchelepi,Amanda Valdiosera,Justin Clubb,Nicole Barbour,Vikram Sisodiya,Joseph Sandoval,Christina Lee,Monette Aujay,Julia Gavrilyuk
摘要
Our previous studies with shishijimicin A resulted in the total synthesis of this scarce marine natural product and a number of its simpler analogues endowed with picomolar potencies against certain cancer cell lines. Herein, we describe the design, synthesis, and biological evaluation of four linker-drugs, anticipating the construction of antibody–drug conjugates (ADCs) as the ultimate goal of this research program. Using a common payload, the assembly of these linker-drugs utilized different linkers and attachment points, providing opportunities to probe the optimal molecular design of the intended ADCs as targeted cancer therapies. In the course of ADC generation and in vitro evaluation, we identified two linker-drugs with a promising in vitro plasma stability profile and excellent targeted cytotoxicity and specificity. Conjugation of shishijimicin A enediyne payloads through their phenolic moiety represents a novel approach to enediyne ADC creation, while the pharmacological profiles of at least two of the generated ADCs compare well with the profiles of the corresponding clinically approved ADC Kadcyla.
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