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Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with L-phenylglycine scaffold

Authors Zhang Y, Li X, Hou J, Huang Y, Xu W

Received 8 August 2015

Accepted for publication 9 September 2015

Published 8 October 2015 Volume 2015:9 Pages 5553—5567


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Wei Duan

Yingjie Zhang,1 Xiaoguang Li,1 Jinning Hou,1 Yongxue Huang,2 Wenfang Xu1

1Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji’nan, 2Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, People’s Republic of China

Abstract: In our previous research, a novel series of histone deacetylase (HDAC) inhibitors with L-phenylglycine scaffold were designed and synthesized, among which amides D3 and D7 and ureido D18 were far superior to the positive control (suberoylanilide hydroxamic acid [SAHA]) in HDAC inhibition, but were only comparable to SAHA in antiproliferation on tumor cell lines. Herein, further structural derivation of lead compounds D3, D7, and D18 was carried out to improve their cellular activities. Most of our newly synthesized compounds exhibited more potent HDAC inhibitory activities than the positive control SAHA, and several derivatives were even better than their parent compounds. However, compared with SAHA and our lead compounds, only secondary amine series compounds exhibited improved antiproliferative activities, likely due to their appropriate topological polar surface area values and cell permeabilities. In a human histiocytic lymphoma (U937) xenograft model, the most potent secondary amine 9d exhibited similar in vivo antitumor activity to that of SAHA.

Keywords: phenylglycine, histone deacetylases, inhibitor, antitumor

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