Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities

详细信息    查看全文

• 作者：Koichi Narita^a ; Yurie Fukui^a ; Yui Sano^a ; Takao Yamori^b ; Akihiro Ito^c ; Minoru Yoshida^c ; Tadashi Katoh^a ; ^{katoh@tohoku-pharm.ac.jp}
• 关键词：Spiruchostatins ; Histone deacetylase inhibitors ; Natural products ; Bicyclic depsipeptide ; Total synthesis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：60
• 期：Complete
• 页码：295-304
• 全文大小：570 K

文摘

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.