Narita Koichi
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University.
Yakugaku Zasshi. 2022;142(9):917-926. doi: 10.1248/yakushi.22-00091.
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.
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）已被批准用于治疗皮肤T细胞淋巴瘤和外周T细胞淋巴瘤。本研究重点在于开发一种新的合成方法来生产这类用作高效低毒HDAC抑制剂的天然产物。本文描述了FK228以及螺旋抑肽素A和B的全合成。合成路线包括一种通过胺片段与羧酸片段的酰胺缩合来组装开链酸的汇聚方法。还描述了C4和C7修饰的FK228类似物（FK-A1至FK-A8）的合成。对合成类似物的HDAC和细胞生长抑制活性的评估揭示了它们构效关系的新方面。鉴定出了强效且高度亚型选择性的HDAC1抑制剂。此外，这些类似物还表现出磷脂酰肌醇3激酶（PI3K）抑制活性。作为HDAC/PI3K双重抑制剂对类似物进行结构优化，从而鉴定出FK-A11是最有效的类似物。
