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Synthesis and Biological Evaluation of Shishijimicin A-Type Linker-Drugs and Antibody–Drug Conjugates
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-07-14 , DOI: 10.1021/jacs.0c06554 K C Nicolaou 1 , Ruofan Li 1 , Qifeng Chen 1 , Zhaoyong Lu 1 , Emmanuel N Pitsinos 1, 2 , Alexander Schammel 3 , Baiwei Lin 3 , Christine Gu 3 , Hetal Sarvaiya 3 , Robert Tchelepi 3 , Amanda Valdiosera 3 , Justin Clubb 3 , Nicole Barbour 3 , Vikram Sisodiya 3 , Joseph Sandoval 3 , Christina Lee 3 , Monette Aujay 3 , Julia Gavrilyuk 3
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-07-14 , DOI: 10.1021/jacs.0c06554 K C Nicolaou 1 , Ruofan Li 1 , Qifeng Chen 1 , Zhaoyong Lu 1 , Emmanuel N Pitsinos 1, 2 , Alexander Schammel 3 , Baiwei Lin 3 , Christine Gu 3 , Hetal Sarvaiya 3 , Robert Tchelepi 3 , Amanda Valdiosera 3 , Justin Clubb 3 , Nicole Barbour 3 , Vikram Sisodiya 3 , Joseph Sandoval 3 , Christina Lee 3 , Monette Aujay 3 , Julia Gavrilyuk 3
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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.
中文翻译：
Shishijimicin A 型接头药物和抗体药物偶联物的合成和生物学评价
我们之前对石狮霉素 A 的研究导致了这种稀有的海洋天然产物及其许多更简单的类似物的全合成，这些类似物具有针对某些癌细胞系的皮摩尔效力。在此，我们描述了四种接头药物的设计、合成和生物学评估，预计抗体药物偶联物 (ADC) 的构建是该研究计划的最终目标。使用共同的有效载荷，这些接头药物的组装利用不同的接头和连接点，为探索作为靶向癌症治疗的预期 ADC 的最佳分子设计提供了机会。在 ADC 生成和体外评估过程中，我们确定了两种接头药物，它们具有良好的体外血浆稳定性和出色的靶向细胞毒性和特异性。
更新日期：2020-07-14
中文翻译：
Shishijimicin A 型接头药物和抗体药物偶联物的合成和生物学评价
我们之前对石狮霉素 A 的研究导致了这种稀有的海洋天然产物及其许多更简单的类似物的全合成，这些类似物具有针对某些癌细胞系的皮摩尔效力。在此，我们描述了四种接头药物的设计、合成和生物学评估，预计抗体药物偶联物 (ADC) 的构建是该研究计划的最终目标。使用共同的有效载荷，这些接头药物的组装利用不同的接头和连接点，为探索作为靶向癌症治疗的预期 ADC 的最佳分子设计提供了机会。在 ADC 生成和体外评估过程中，我们确定了两种接头药物，它们具有良好的体外血浆稳定性和出色的靶向细胞毒性和特异性。
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