Design and synthesis of mono and bicyclic tetrapeptides thioester as potent inhibitor of histone deacetylases

Amino Acids - Tập 46 - Trang 2435-2444 - 2014
Md. Ashraful Hoque1,2,3, Md. Shahidul Islam3,4, Md. Nurul Islam3,4, Tamaki Kato3, Norikazu Nishino3, Akihiro Ito5, Minoru Yoshida5
1Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Malaysia
2Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi, Bangladesh
3Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
4Department of Chemistry, Faculty of Science, University of Rajshahi, Rajshahi, Bangladesh
5RIKEN, Saitama, Japan

Tóm tắt

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that have an effect on gene regulation. The naturally occurring cyclic depsipeptide FK228 containing disulfide and Largazole possessing thioester functionalities act as pro-drugs and share the same HDAC inhibition mechanism in cell. Inspired from these facts, we have reported bicyclic tetrapeptide disulfide HDAC inhibitors resembling FK228 with potent activity and enhanced selectivity. In the present study, we report the design and synthesis of several mono and bicyclic tetrapeptide thioester HDAC inhibitors that share the inhibition mechanism similar to Largazole. Most of the compounds showed HDAC1 and HDAC4 inhibition and p21 promoting activity in nanomolar ranges. Among these the monocyclic peptides 1, 2 and bicyclic peptide, 4 are notable demanding more advanced research to be promising anticancer drug candidates.

Tài liệu tham khảo

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