Total Synthesis of AMF-26, an Antitumor Agent for Inhibition of the Golgi System, Targeting ADP-Ribosylation Factor 1

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• 作者：Isamu Shiina ; Yuma Umezaki ; Yoshimi Ohashi ; Yuta Yamazaki ; Shingo Dan ; Takao Yamori
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：150-159
• 全文大小：761K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

An effective method for the total synthesis of 1 (AMF-26), a potentially promising new anticancer drug that disrupts the Golgi system by inhibiting the ADP-ribosylation factor 1 (Arf1) activation, has been developed for the first time. The construction of the chiral linear precursor (a key to the synthesis) was achieved by the asymmetric aldol reaction followed by the computer-assisted predictive stereoselective intramolecular Diels鈥揂lder reaction. The global antitumor activity of the totally synthetic 1 against a variety of human cancer cells was assessed using a panel of 39 human cancer cell lines (JFCR39), and it was shown that the synthetic 1 strongly inhibited the growth of several cancer cell lines at concentrations of less than 0.04 渭M. Biological assays of novel derivatives, 26 and 31, which have different side-chains at the C-4 positions in the 螖^1,2-octalin backbone, disclosed the importance of the suitable structure of the side-chain containing conjugated multidouble bonds.