Department of Chemistry, Stanford University, Stanford, California 94305, United States.
Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305, United States.
J Org Chem. 2020 Dec 4;85(23):15116-15128. doi: 10.1021/acs.joc.0c01988. Epub 2020 Nov 17.
Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin's A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with 's < 5 nM, while the latter exhibited PKC affinities that were up to ∼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics , indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators.
采用基于功能的合成策略，我们设计、合成并评估了迄今报道的最简单的 bryostatin 1 类似物，其中 bryostatin 的 A-和 B-环被戊二酸盐连接子取代。这些类似物中，一个没有，一个有 C26-甲基，对蛋白激酶 C（PKC）同工型的亲和力有明显不同。前者对几种 PKC 同工型表现出 bryostatin 样结合，其结合常数 's < 5 nM，而后者对 PKC 的亲和力低 180 倍。具有 bryostatin 样 PKC 亲和力的类似物也表现出 bryostatin 样的 PKC 易位动力学，表明其具有快速的细胞渗透性，并与 PKC 靶标结合。这项研究例证了基于功能的合成策略的强大之处，通过活性导向设计降低结构复杂性，从而提高合成可及性，同时保持功能（生物活性），为解决 PKC 调节剂日益增多的治疗适应症提供了新的线索。
