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.

中文翻译：

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发现 N-(2-氨基苯基)-4-(双(2-氯乙基)氨基)苯甲酰胺作为有效的组蛋白脱乙酰酶抑制剂。

组蛋白脱乙酰酶（HDAC）的抑制已成为治疗多种癌症的重要新兴疗法。然而，HDAC抑制剂的应用因对抗实体瘤的效力有限而受到限制。为了发现具有有效抗肿瘤活性的新型HDAC抑制剂，在CI994的结构中引入了氮芥基团。衍生分子 N-(2-氨基苯基)-4-(双(2-氯乙基)氨基)苯甲酰胺 (NA) 对 HDAC1、HDAC2、和HDAC3，分别。在抗增殖测定中，NA 对 A2780 和 HepG2 细胞生长的抑制作用分别比辛二酰苯胺异羟肟酸 (SAHA)（27.3 和 19.5 μM）高 10.3 倍（2.66 μM）和 11.3 倍（1.73 μM）。进一步基于 HepG2 细胞的细胞周期和细胞凋亡研究表明，诱导 G2/M 期停滞和细胞凋亡有助于 NA 的抗肿瘤作用。建议NA可以作为先导化合物来开发用于治疗实体瘤的双功能HDAC抑制剂。