Synthesis and Biological Evaluation of Shishijimicin A‑Type Linker-Drugs and Antibody–Drug Conjugates

• Published in: Journal of the American Chemical Society Vol. 142; no. 29; pp. 12890 - 12899
• Main Authors: Nicolaou, K. C, Li, Ruofan, Chen, Qifeng, Lu, Zhaoyong, Pitsinos, Emmanuel N, Schammel, Alexander, Lin, Baiwei, Gu, Christine, Sarvaiya, Hetal, Tchelepi, Robert, Valdiosera, Amanda, Clubb, Justin, Barbour, Nicole, Sisodiya, Vikram, Sandoval, Joseph, Lee, Christina, Aujay, Monette, Gavrilyuk, Julia
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.07.2020; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Cell Survival - drug effects; Chemistry; Chemistry, Multidisciplinary; Disaccharides - chemical synthesis; Disaccharides - chemistry; Disaccharides - pharmacology; Drug Design; Enediynes - chemical synthesis; Enediynes - chemistry; Enediynes - pharmacology; HEK293 Cells; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Molecular Structure; Physical Sciences; Science & Technology; CHEMISTRY; ANTITUMOR ANTIBIOTICS; POTENT; GENERATION; CALICHEMICINS; FAMILY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c06554

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.