Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Eur J Med Chem. 2013 Feb;60:295-304. doi: 10.1016/j.ejmech.2012.12.023. Epub 2012 Dec 21.
The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a D-leucine-D-cysteine- or D-valine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin). Novel aspects of structure-activity relationships (SAR) were revealed.
首次以高度收敛和统一的方式合成了双环脱肽组蛋白去乙酰化酶 (HDAC) 抑制剂螺旋甾酮 C 和 D。该方法的特点是将含有 D-亮氨酸-D-半胱氨酸或 D-缬氨酸-D-半胱氨酸的片段与含有 D-丙氨酸或 D-缬氨酸的片段进行酰胺偶联，直接组装相应的 sec 酸，这是大环内酯化的关键前体。合成的脱肽化合物的 HDAC 抑制测定和细胞生长抑制分析确定了与临床批准的脱肽化合物 FK228（罗米地辛）相比螺旋甾酮 A-D 的效力顺序。揭示了结构-活性关系 (SAR) 的新方面。
