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

Bingbing Zhang,Qiang Sui,Zhu-Wei Ruan,Dongdong Luo,Yueyue Zhu,Xinsheng Lei,Tingbo Ding

doi:10.3390/md18070344

Abstract

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.

Highlights

Both histone acetyltransferases (HATs) and histone deacetylases (HDACs) play a key role in the regulation of histone-tailed lysine acetylation status, which is closely associated with cell processes [1].Up to now, 18 HDAC isoforms have been identified and divided into four classes, including theZn2+ -dependent Class I (HDAC1, 2, 3, 8), Class II (HDAC4–7, 9–10), Class IV (HDAC11), and NAD+dependent Class III [2]
When they replaced Val with a set of residues tagged with the terminal amine or residues withsuggested the terminal or amides, the results suggested that theanhydrogen bonding amides,tagged the results thatamine the hydrogen bonding interaction did not play essential role in interaction did not play an essential role in
Asobservations our researchreported continued, we discovered to our our surprise that the replacement of Val surprise that the replacement of Val with

Summary

Introduction

Both histone acetyltransferases (HATs) and histone deacetylases (HDACs) play a key role in the regulation of histone-tailed lysine acetylation status, which is closely associated with cell processes [1].Up to now, 18 HDAC isoforms have been identified and divided into four classes, including theZn2+ -dependent Class I (HDAC1, 2, 3, 8), Class II (HDAC4–7, 9–10), Class IV (HDAC11), and NAD+dependent Class III (namely SIRT1-7) [2]. 18 HDAC isoforms have been identified and divided into four classes, including the. The function of individual HDAC isoform is not fully understood in cells, HDACs have become an appealing target in cancer therapy through balancing histone hypoacetylation and overexpression of HDACs in multiple cancers. Zn2+ -dependent HDAC inhibitors, such as SAHA (Vorinostat), Belinostat, Panobinostat, Chidamide and Romidepsin (FK228), have been approved for the treatment of cutaneous T-cell lymphoma. These inhibitors are pan-selective inhibitors [3,4]. The current trend is to explore potent and selective HDAC inhibitors [5,6,7]

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Results

Conclusion