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Open AccessArticle

Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole

1
School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China
2
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
3
China State Institute of Pharmaceutical Industry, No. 285 Gebaini Road, Pudong Zone, Shanghai 201203, China
4
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Mar. Drugs 2020, 18(7), 344; https://doi.org/10.3390/md18070344
Received: 30 May 2020 / Revised: 23 June 2020 / Accepted: 28 June 2020 / Published: 30 June 2020
Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole’s macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five–nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol. A molecular modeling study provided rational explanation and structural evidence for the enhanced inhibitory activity. This new finding will aid the design of novel potent HDAC inhibitors. View Full-Text
Keywords: marine natural product; largazole; HDAC inhibitors; modification; fluoro olefin marine natural product; largazole; HDAC inhibitors; modification; fluoro olefin
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MDPI and ACS Style

Zhang, B.; Ruan, Z.-W.; Luo, D.; Zhu, Y.; Ding, T.; Sui, Q.; Lei, X. Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole. Mar. Drugs 2020, 18, 344.

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