Abstract :
Improved, streamlined total syntheses of natural tubulysins such as V (Tb45) and U (Tb46) and pretubulysin D (PTb-D43), and their application to the synthesis of designed tubulysin analogues (Tb44, PTb-D42, PTb-D47-PTb-D49, and Tb50-Tb120), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines reveal a number of novel analogues with exceptional potencies [e.g., Tb111: IC50 = 40 pM against MES SA (uterine sarcoma) cell line.The extremely potent cytotoxic compounds discovered in the investigations are highly desirable as potential payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.