Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

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• 作者：K. C. Nicolaou ; Jun Yin ; Debashis Mandal ; Rohan D. Erande ; Philipp Klahn ; Michael Jin ; Monette Aujay ; Joseph Sandoval ; Julia Gavrilyuk ; Dionisios Vourloumis
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：February 10, 2016
• 年：2016
• 卷：138
• 期：5
• 页码：1698-1708
• 全文大小：1162K
• ISSN：1520-5126

文摘

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.