Wender Paul A, Hardman Clayton T, Ho Stephen, Jeffreys Matthew S, Maclaren Jana K, Quiroz Ryan V, Ryckbosch Steven M, Shimizu Akira J, Sloane Jack L, Stevens Matthew C
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Science. 2017 Oct 13;358(6360):218-223. doi: 10.1126/science.aan7969.
Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.
苔藓抑素1是一种极为稀有的海洋天然产物，目前正处于临床开发阶段，用于根除艾滋病毒/艾滋病、癌症免疫治疗和治疗阿尔茨海默病。尽管有这一独特的适应症组合，但其可得性一直有限且不稳定，从而阻碍了研究和临床研究。在此，我们报告了苔藓抑素1的全合成，该合成总共进行29步（最长线性序列为19步，每步平均产率>80%），总共可生产克级的产物，并且可以扩大规模以满足临床需求（每年约20克）。这种解决苔藓抑素供应问题的实用方法还为衍生物和潜在的更优类似物提供了广泛、简便且高效的获取途径。
