Discovery of class I histone deacetylase inhibitors based on romidpesin with promising selectivity for cancer cells.
Aim: Class I histone deacetylases (HDACs) are considered to be promising anticancer targets, but selective inhibition of class I HDAC isoforms remains a challenge. Methods & results: Previously, we obtained a selective class I HDAC inhibitor 9 based on a macrocyclic HDAC inhibitor Romidpesin. As our continuous efforts, a library of novel cyclicdepsipeptides based on 9 was established using a convergent synthesis strategy. The most active compounds 10, 16 and 19 selectively inhibit class I HDACs and exhibit promising nanomolar antiproliferative activities against several cancer cell lines with excellent selectivity toward cancer cells over normal cells. Besides, compound 10 demonstrates excellent antitumor effects in human prostate carcinoma PC3 xenograft models with no observed toxicity. Conclusion: These cyclicdepsipeptides show great therapeutic potential as novel anticancer agents for clinical translation.
['Zhang|Kuojun|K|', 'Yao|Yiwu|Y|', 'Tu|Zhengchao|Z|', 'Liao|Chenzhong|C|', 'Wang|Zhen|Z|', 'Qiu|Yatao|Y|', 'Chen|Dong|D|', 'Hamilton|Dale J|DJ|', 'Li|Zheng|Z|', 'Jiang|Sheng|S|0000-0002-4550-5024']
D000818:Animals D000970:Antineoplastic Agents D049109:Cell Proliferation D047630:Depsipeptides D004305:Dose-Response Relationship, Drug D055808:Drug Discovery D004354:Drug Screening Assays, Antitumor D056572:Histone Deacetylase Inhibitors D006655:Histone Deacetylases D006801:Humans D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008958:Models, Molecular D008968:Molecular Conformation D009374:Neoplasms, Experimental D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
class I histone deacetylases inhibitor antitumor cyclic depsipeptides structure–activity relationship