Total Synthesis and Biological Evaluation of Cortistatins A and J and Analogues Thereof

详细信息    查看全文

• 作者：K. C. Nicolaou ; Xiao-Shui Peng ; Ya-Ping Sun ; Damien Polet ; Bin Zou ; Chek Shik Lim ; David Y.-K. Chen
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：August 5, 2009
• 年：2009
• 卷：131
• 期：30
• 页码：10587-10597
• 全文大小：631K
• 年卷期：v.131,no.30(August 5, 2009)
• ISSN：1520-5126

文摘

Total syntheses of the highly selective antiproliferative natural products cortistatins A (1) and J (5) in their naturally occurring enantiomeric forms are described. The modular and convergent strategy employed relies on an intramolecular oxa-Michael addition/aldol/dehydration cascade reaction to cast the ABCD ring framework of the molecule and both Sonogashira and Suzuki−Miyaura coupling reactions to assemble the necessary building blocks into the required heptacyclic skeleton. A divergent approach from a late-stage epoxy ketone leads to both target molecules in a stereoselective manner. The developed synthetic technologies were applied to the construction of several analogues of the cortistatins which were biologically evaluated and compared to the natural products with regards to their antiproliferative activities against a variety of cancer cells. Analogues 8 and 81, lacking both the dimethylamino and hydroxyl groups of cortistatin A, were found to exhibit comparable biological activity as the parent compound, leading to the conclusion that such functionalities are not essential for biological activity.