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. 2017 Jun 15;25(12):3077-3086.
doi: 10.1016/j.bmc.2017.03.071. Epub 2017 Apr 4.

Synthesis and biological evaluation of largazole zinc-binding group analogs

Bumki Kim  1 , Ranjala Ratnayake  2 , Hyunji Lee  1 , Guqin Shi  3 , Sabrina L Zeller  1 , Chenglong Li  2 , Hendrik Luesch  4 , Jiyong Hong  5
Affiliations

Synthesis and biological evaluation of largazole zinc-binding group analogs

Bumki Kim et al. Bioorg Med Chem. .

Abstract

Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity. However, previous structure-activity relationship studies have heavily investigated the macrocycle region of largazole, while there have been only limited efforts to probe the effect of various zinc-binding groups (ZBGs) on HDAC inhibition. Herein, we prepared a series of largazole analogs with various ZBGs and evaluated their HDAC inhibition and cytotoxicity. While none of the analogs tested were as potent or selective as largazole, the Zn2+-binding affinity of each ZBG correlated with HDAC inhibition and cytotoxicity. We expect that our findings will aid in building a deeper understanding of the role of ZBGs in HDAC inhibition as well as provide an important basis for the future development of new largazole analogs with non-thiol ZBGs as novel therapeutics for cancer.

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Figures

Figure 1
Figure 1
Representative HDAC inhibitors.
Figure 2
Figure 2
The mechanism of action of largazole (5).
Figure 3
Figure 3
Structure of largazole thiol (6) and ZBG analogs 7–13.
Figure 4
Figure 4
An initial synthetic approach to largazole ZBG analogs 7–13.
Figure 5
Figure 5
A revised synthetic approach to largazole ZBG analogs 7–12.
Figure 6
Figure 6
Cytotoxicity and in vitro monitoring of histone hyperacetylation for largazole (5) and high-affinity ZBG analogs (7 and 8). (A) Cell viability of HCT116 and MDA-MB-231 cells was determined after a 48 h-exposure to compound using MTT assay. Histone hyperacetylation in cells was monitored after 8 h-exposure to compound: (B) largazole and (C) analogs 7 and 8; protein lysates were collected and analyzed by immunoblot analysis for histone H3 (Lys9/14) acetylation.
Figure 7
Figure 7
Top (left) and side (right) views of largazole thiol (6) docking model in HDAC1 active site. Light Gray: HDAC1. Cyan: Largazole thiol (6) docking model. Coral: Crystal structure of largazole thiol (6) co-crystallized with HDAC8 (PDB: 3RQD) superimposed with docking model.
Figure 8
Figure 8
Two potential binding modes of analog 7 with HDAC1 generated by AutoDock4.
Figure 9
Figure 9
A potential binding mode of analog 8 with HDAC1 generated by AutoDock4.
Scheme 1
Scheme 1
Synthesis of the alkyl analog 13.
Scheme 2
Scheme 2
Synthesis of the ketone analog 11, carboxylic acid analog 12, and hydroxamic acid analog 7.
Scheme 3
Scheme 3
Synthesis of the mercaptosulfide analog 8.
Scheme 4
Scheme 4
Synthesis of the amine analog 9 and β-ketoamide analog 10.
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