| Literature DB >> 26829208 |
K C Nicolaou1, Jun Yin1, Debashis Mandal1, Rohan D Erande1, Philipp Klahn1, Michael Jin1, Monette Aujay2, Joseph Sandoval2, Julia Gavrilyuk2, Dionisios Vourloumis1,3.
Abstract
A streamlined total synthesis of N(14)-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.Entities:
Mesh：
Substances：
Year: 2016 PMID： 26829208 DOI： 10.1021/jacs.5b12557
Source DB: PubMed Journal: J Am Chem Soc ISSN： 0002-7863 Impact factor: 15.419