Stabilized Cyclopropane Analogs of the Splicing Inhibitor FD-895

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• 作者：Reymundo Villa ; Manoj Kumar Kashyap ; Deepak Kumar ; Thomas J. Kipps ; Januario E. Castro ; James J. La Clair ; Michael D. Burkart
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6576-6582
• 全文大小：416K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Targeting the spliceosome with small molecule inhibitors provides a new avenue to target cancer by intercepting alternate splicing pathways. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. These findings have encouraged recent academic and industrial efforts to develop natural product spliceosome inhibitors, including FD-895 (1a), pladienolide B (1b), and pladienolide D (1c), into next-generation anticancer drugs. The present study describes the application of semisynthesis and total synthesis to reveal key structure鈥揳ctivity relationships for the spliceosome inhibition by 1a. This information is applied to deliver new analogs with improved stability and potent activity at inhibiting splicing in patient derived cell lines.