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Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody-Drug Conjugates
K.C. Nicolaou, , J. Yin, D. Vourloumis, M. Aujay, J. Sandoval, S. Munneke, J. Gavrilyuk
Published in American Chemical Society
PMID: 29381062
Volume: 140
Issue: 10
Pages: 3690 - 3711
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 revealed a number of novel analogues with exceptional potencies [e.g., Tb111: IC50 = 40 pM against MES SA (uterine sarcoma) cell line; IC50 = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC50 = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure-activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies. © 2018 American Chemical Society.
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JournalData powered by TypesetJournal of the American Chemical Society
PublisherData powered by TypesetAmerican Chemical Society