Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations
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- 作者：K. C. Nicolaou ; Yanping Wang ; Min Lu ; Debashis Mandal ; Manas R. Pattanayak ; Ruocheng Yu ; Akshay A. Shah ; Jason S. Chen ; Hongjun Zhang ; James J. Crawford ; Laxman Pasunoori ; Yam B. Poudel ; Naidu S. Chowdari ; Chin Pan ; Ayesha Nazeer ; Sanjeev Gangwar ; Gregory Vite ; Emmanuel N. Pitsinos
- 刊名：Journal of the American Chemical Society
- 出版年：2016
- 出版时间：July 6, 2016
- 年：2016
- 卷：138
- 期：26
- 页码：8235-8246
- 全文大小：903K
- 年卷期：0
- ISSN：1520-5126
文摘
From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.