Discovery of N-(2-Aminophenyl)-4-(bis(2-chloroethyl)amino)Benzamide as a Potent Histone Deacetylase Inhibitor

Lihui Zhang; Xiaoyang Li; Yiming Chen; Minghui Wan; Qixiao Jiang; Li Zhang; C James Chou; Weiguo Song; Lei Zhang

doi:10.3389/fphar.2019.00957

Discovery of N-(2-Aminophenyl)-4-(bis(2-chloroethyl)amino)Benzamide as a Potent Histone Deacetylase Inhibitor

Front Pharmacol. 2019 Aug 30:10:957. doi: 10.3389/fphar.2019.00957. eCollection 2019.

Authors

Lihui Zhang¹, Xiaoyang Li², Yiming Chen³, Minghui Wan³, Qixiao Jiang⁴, Li Zhang⁵, C James Chou⁶, Weiguo Song³, Lei Zhang³

Affiliations

¹ School of Stomatology, Weifang Medical University, Weifang, China.
² School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
³ Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China.
⁴ School of Public Health, Qingdao University, Qingdao, China.
⁵ School of Pharmacy, Qingdao University, Qingdao, China.
⁶ Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC, United States.

Abstract

Inhibition of histone deacetylases (HDACs) has been an important emerging therapy for the treatment of multiple cancers. However, the 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, 260.7, 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 did suberoylanilide hydroxamic acid (SAHA) (27.3 and 19.5 μM) in inhibition of A2780 and HepG2 cell growth, respectively. Further HepG2 cell-based cell cycle and apoptosis studies revealed that induction of the G2/M phase arrest and cell apoptosis contributes 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; antitumor; inhibitor; nitrogen mustard; selectivity.