Design,synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents |
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Institution: | 1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam;2. School of Medicine and Pharmacy, Hanoi National University, 144 Xuan Thuy, Hanoi, Viet Nam;3. College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea;4. Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea;5. School of Chemical Engineering, Hanoi University of Science and Technology, 1 Dai Co Viet, Hanoi, Viet Nam;1. Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji''nan, Shandong, 250012, PR China;2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;3. Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States;4. Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China;1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India;2. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland;3. Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 2014, Aljouf, Saudi Arabia;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;5. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;6. Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, 71526 Assiut, Egypt;8. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt;1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam;2. School of Chemical Engineering, Hanoi University of Science and Technology, No. 1 Dai Co Viet, Hai Ba Trung, Hanoi, Viet Nam;3. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;4. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea |
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Abstract: | In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R2 ~ 95%) with experimental results. |
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Keywords: | Histone deacetylase (HDAC) inhibitors Hydroxamic acids |
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