Abstract：
Bicyclic depsipeptide natural products containing an intramolecular disulfide bond are potent histone deacetylase (HDAC) inhibitors. Among them, FK228 (romidepsin) is approved for treating cutaneous T-cell lymphoma and peripheral T-cell lymphoma. This study focused on developing a new synthesis method for producing this class of natural products for use as HDAC inhibitors with high efficacy and low toxicity. In this paper, the total syntheses of FK228 as well as spiruchostatins A and B are described. The synthesis routes include a convergent way to assemble seco-acids via the amide condensation of amine segments with carboxylic acid segments. The syntheses of C4- and C7-modified FK228 analogs (FK-A1 to FK-A8) are also described. The evaluation of HDAC and cell growth inhibitory activities of the synthesized analogs revealed novel aspects of their structure-activity relationship. Potent and highly isoform-selective HDAC1 inhibitors were identified. Furthermore, the analogs showed phosphatidylinositol 3-kinase (PI3K) inhibitory activity. Structural optimization of the analogs as HDAC/PI3K dual inhibitors led to the identification of FK-A11 as the most potent analog.
摘要：
含有分子内二硫键的双环缩肽天然产物是有效的组蛋白脱乙酰酶(HDAC)抑制剂。其中,FK228（罗米地辛）被批准用于治疗皮肤T细胞淋巴瘤和外周T细胞淋巴瘤。这项研究的重点是开发一种新的合成方法，用于生产此类天然产物，用作高效低毒的HDAC抑制剂。在本文中,描述了FK228以及螺旋体抑制素A和B的总合成。合成路线包括通过胺链段与羧酸链段的酰胺缩合来组装酸的会聚方式。还描述了C4-和C7-修饰的FK228类似物(FK-A1至FK-A8)的合成。对HDAC和合成类似物的细胞生长抑制活性的评估揭示了它们的结构-活性关系的新方面。鉴定了有效和高度同工型选择性的HDAC1抑制剂。此外，类似物显示磷脂酰肌醇3-激酶(PI3K)抑制活性。作为HDAC/PI3K双重抑制剂的类似物的结构优化导致FK-A11被鉴定为最有效的类似物。
