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Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins
K.C. Nicolaou, J. Yin, D. Mandal, , P. Klahn, M. Jin, M. Aujay, J. Sandoval, J. Gavrilyuk, D. Vourloumis
Published in American Chemical Society
PMID: 26829208
Volume: 138
Issue: 5
Pages: 1698 - 1708
A streamlined total synthesis of N14-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies. © 2016 American Chemical Society.
About the journal
JournalData powered by TypesetJournal of the American Chemical Society
PublisherData powered by TypesetAmerican Chemical Society