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Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents

[ Vol. 19 , Issue. 4 ]

Author(s):

Duong T. Anh, Nguyen T. Thuan, Pham-The Hai, Le-Thi-Thu Huong, Nguyen T.K. Yen, Byung W. Han, Eun J. Park, Yeo J. Choi, Jong S. Kang, Van T.M. Hue*, Sang-Bae Han* and Nguyen-Hai Nam*   Pages 546 - 556 ( 11 )

Abstract:


Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101).

Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines.

Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships.

Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities.

Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

Keywords:

Histone deacetylase (HDAC) inhibitors, hydroxamic acids, N-hydroxybenzamide, N-hydroxypropenamide, molecular docking, inhibitory potency.

Affiliation:

Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, School of Medicine and Pharmacy, Vietnam National University, 144 Xuan Thuy, Hanoi, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk, 28160, College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk, 28160, Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do 28116, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk, 28160, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi

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