Structure-Activity Relationship Study of New FK228 Analogues as Antitumor Agents

摘要

Histone deacetylases (HDACs) are a family of enzymes that play a crucial role in regulating numerous vital functions by influencing on gene expression through the modification of chromosomal DNA conformation. They are typically grouped into four classes, and classes I, II and IV are characterized to have Zn~(2+) as a critical component at their active sites, whereas class III HDACs distinctly use a cofactor, NAD~+ [1]. In the past two decades, many studies showed a correlation between an increased activity of Zn~(2+)-dependent HDACs and tumorigenesis processes, and this makes HDACs a new attractive therapeutic target for cancer treatment [2]. A number of small molecules have been identified or developed as HDAC inhibitors that trigger cell cycle arrest, differentiation, and apoptosis in cancer cells [3], Isolated from Chromobacterium violaceum, FK228 (also known as FR901,228 or depsipeptide) is a highly potent inhibitor with selectivity toward class I HDACs that appears to be more relevant for intervention in oncology [4,5]. Despite its promising therapeutic profile, FK228 has a unique bicyclic structure and several synthetically challenging moieties. These synthetic difficulties prevented the synthesis of FK228 analogues that would promote the understanding of the molecular mechanism underling its anti-cancer activity.