Synthesis of seco-B-Ring Bryostatin Analogue WN-1 via C鈥揅 Bond-Forming Hydrogenation: Critical Contribution of the B-Ring in Determining Bryostatin-like and Phorbol 12-Myristate 13-Acetate-like

详细信息    查看全文

• 作者：Ian P. Andrews ; John M. Ketcham ; Peter M. Blumberg ; Noemi Kedei ; Nancy E. Lewin ; Megan L. Peach ; Michael J. Krische
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：September 24, 2014
• 年：2014
• 卷：136
• 期：38
• 页码：13209-13216
• 全文大小：668K
• ISSN：1520-5126

文摘

The seco-B-ring bryostatin analogue, macrodiolide <b>WN-1b>, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C鈥揅 coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a Cb>2b>-symmetric diol to form the C9-deoxygenated bryostatin A-ring. <b>WN-1b> binds to PKC伪 (Kb>ib> = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the <b>WN-1b> A-ring and C-ring are shared by analogues that display bryostatin-like behavior, <b>WN-1b> displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in <b>WN-1b>, and that upon docking <b>WN-1b> into the crystal structure of the C1b domain of PKC未, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.