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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00957

Discovery of N-(2-aminophenyl)-4-(bis(2-chloroethyl)amino)benzamide as a potent histone deacetylase inhibitor

Lihui Zhang1, Xiaoyang Li2, Yiming Chen1, Minghui Wan1, Qixiao Jiang3, Li zhang3, C. James Chou4,  Weiguo Song1 and  Lei Zhang1*
  • 1Weifang Medical University, China
  • 2Ocean University of China, China
  • 3Qingdao University, China
  • 4Medical University of South Carolina, United States

Inhibition of HDACs have been an important emerging therapy for the treatment of multiple cancers. However, the wide application of HDAC inhibitors is restricted by the limited potency against solid tumors. In order to discover novel HDAC inhibitors with potent antitumor activities, nitrogen mustard group was introduced to the structure of CI994. The derived molecule N-(2-aminophenyl)-4-(bis(2-chloroethyl)amino)benzamide (NA) exhibited enzyme inhibitory pattern of class I selectivity with IC50 values of 95.2 nM, 260.7 nM and 255.7 nM against HDAC1, HDAC2 and HDAC3, respectively. In the antiproliferative assay, NA exhibited 10.3-fold (2.66 μM) and 11.3-fold (1.73 μM) higher potency than SAHA (27.3 and 19.5 μM) in inhibition the growth of A2780 and HepG2 cells, respectively. Further HepG2 cell based cell cycle and apoptosis studies revealed that induction of G2/M phase arrest and cell apoptosis makes contributions to the antitumor effects of NA. It is suggested that NA could be utilized as a lead compound in the development of bifunctional HDAC inhibitors for the treatment of solid tumors.

Keywords: HDAC, inhibitor, Nitrogen mustard, antitumor, Selectivity

Received: 06 May 2019; Accepted: 26 Jul 2019.

Copyright: © 2019 Zhang, Li, Chen, Wan, Jiang, zhang, Chou, Song and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Lei Zhang, Weifang Medical University, Weifang, 261053, Shandong Province, China,