Zong Guanghui, Hu Zhijian, Duah Kwabena Baffour, Andrews Lauren E, Zhou Jianhong, O'Keefe Sarah, Whisenhunt Lucas, Shim Joong Sup, Du Yuchun, High Stephen, Shi Wei Q
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States.
Angion Biomedica Corp., 51 Charles Lindbergh Boulevard, Uniondale, New York 11553, United States.
J Org Chem. 2020 Dec 18;85(24):16226-16235. doi: 10.1021/acs.joc.0c01659. Epub 2020 Dec 2.
Two new ring-size-varying analogues ( and ) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC: from 1.8 nM) and in vitro protein translocation inhibition (IC: 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: ∼3 mg/kg).
合成并评估了异波豆素 F 的两种新的环大小可变类似物（和）。环扩展带来的细胞毒性改善（IC：从 1.8 nM 起）和体外蛋白质易位抑制（IC：35 nM）表明，Sec61α（亚型 1）的结合口袋可以容纳进一步的结构修饰，可能在脂肪酸部分。关键二醇中间体的简化制备实现了克级生产，使我们能够确定异波豆素 F 在体内具有生物活性（最大耐受剂量：约 3 mg/kg）。
