Synthesis and Biological Investigation of Δ12-Prostaglandin J3 (Δ12-PGJ3) Analogues and Related Compounds

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• 作者：K. C. Nicolaou ; Kiran Kumar Pulukuri ; Stephan Rigol ; Philipp Heretsch ; Ruocheng Yu ; Charles I. Grove ; Christopher R. H. Hale ; Abdelatif ElMarrouni ; Verena Fetz ; Mark Brönstrup ; Monette Aujay ; Joseph Sandoval ; Julia Gavrilyuk
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：May 25, 2016
• 年：2016
• 卷：138
• 期：20
• 页码：6550-6560
• 全文大小：1071K
• 年卷期：0
• ISSN：1520-5126

文摘

A series of Δ¹²-prostaglandin J₃ (Δ¹²-PGJ₃) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure–activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.