Novel (E)-3-(3-Oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides as Histone Deacetylase Inhibitors: Design,Synthesis and Bioevaluation |
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Authors: | Doan Minh Sang Ik Ho Na Dr Duong Tien Anh Do Thi Mai Dung Nguyen Thi Thu Hang Nguyen T Phuong-Anh Assoc?Prof?Dr Pham-The Hai Assoc?Prof?Dr Dao Thi Kim Oanh Dr Truong Thanh Tung Soo Jung Lee Joo Hee Kwon Prof?Dr Jong Soon Kang Prof?Dr Sang-Bae Han Assoc?Prof?Dr Dinh Thi Thanh Hai Prof?Dr Nguyen-Hai Nam |
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Institution: | 1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, 10000 Vietnam;2. College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk, 28160 Republic of Korea;3. Faculty of Pharmacy, PHENIKAA University, Hanoi, 12116 Vietnam;4. Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, 28160 Republic of Korea |
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Abstract: | Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzob]1,4]oxazin-6-yl)-N-hydroxypropenamides ( 4 a – i , 7 a – g ) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI?H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a – i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a – g in all biological assays. Compounds 7 e – f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity. |
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Keywords: | benzoxazine docking simulation Histone deacetylase (HDAC) inhibitors hydroxamic acids hydroxypropenamides |
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