Narita Koichi, Matsuhara Keisuke, Itoh Jun, Akiyama Yui, Dan Singo, Yamori Takao, Ito Akihiro, Yoshida Minoru, Katoh Tadashi
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Eur J Med Chem. 2016 Oct 4;121:592-609. doi: 10.1016/j.ejmech.2016.05.031. Epub 2016 May 18.
Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified.
新型C4和C7修饰的FK228类似物以高度汇聚和统一的方式高效合成。该合成方法的特点是含甘氨酸 - D - 半胱氨酸片段与含D - 缬氨酸片段进行酰胺缩合，以直接组装相应的开环酸，这些开环酸是大环内酯的关键前体。对合成类似物的HDAC抑制测定和细胞生长抑制分析揭示了它们构效关系的新方面。本研究表明，FK228中C4和C7侧链的简单修饰对于提高HDAC抑制活性和亚型选择性均有效；此外，还鉴定出了强效且高度亚型选择性的I类HDAC1抑制剂。
