Journal
FUTURE MEDICINAL CHEMISTRY
Volume 12, Issue 4, Pages 311-324Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2019-0290
Keywords
antitumor; class I histone deacetylases; cyclic depsipeptides; inhibitor; structure-activity relationship
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Funding
- National Natural Science Foundation [81773559, 21807114]
- Double First-Class University Project [CPU2018GY03]
- International Cooperation Grant of Guangzhou [201704030099]
- Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZRC201810]
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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. Graphical abstract
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