Yurek-George Alexander, Habens Fay, Brimmell Matthew, Packham Graham, Ganesan A
School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
J Am Chem Soc. 2004 Feb 4;126(4):1030-1. doi: 10.1021/ja039258q.
The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.
完成了螺旋抑素A的全合成，明确证实了其结构。关键步骤包括使用长谷硫代噻唑烷辅助剂进行非对映选择性乙酸酯羟醛反应，并作为用于形成酰胺的活化酰化剂，以及通过山口方法进行大环内酯化。结果表明，螺旋抑素A具有与FK228相似的生物活性，FK228是一种在临床试验中有效的组蛋白脱乙酰酶（HDAC）抑制剂。在β-羟基酸处为差向异构体的螺旋抑素A类似物无活性，突出了该位置的立体化学对于与HDAC相互作用的重要性。
