Discovery of novel chalcone-dithiocarbamates as ROS-mediated apoptosis inducers by inhibiting catalase |
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| Institution: | 1. School of Basic Medical Science, Zhengzhou University, Zhengzhou 450001, China;2. School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China;3. Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;4. Department of Urology, University of California, Irvine, Orange, CA 92868, USA;1. Department of Chemistry, Government College University, Faisalabad 38000, Pakistan;2. Department of Chemistry, Government College Women University, Faisalabad, Pakistan;3. Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan;4. Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan;5. Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan;6. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Emory University School of Medicine/Veterans Affairs Medical Center, 1760 Haygood Drive, Atlanta, GA 30322, USA;7. School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, UK;1. Material Science Innovation and Modelling (MaSIM) Research Focus Area, Faculty of Natural and Agricultural Science, North-West University (Mafikeng Campus), Private Bag X2046, Mmabatho, South Africa;2. Department of Chemistry, Faculty of Natural and Agricultural, Science, North-West University (Mafikeng Campus), Private Bag X2046, Mmabatho 2735, South Africa;3. Non-Viral Gene and Drug Delivery Laboratory, Department of Biochemistry, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. New Drug Research & Development Center, North China Pharmaceutical Group Corporation, Shijiazhuang 050015, China;1. Department of Chemistry, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran;2. Department of Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran;3. Department of Chemical Engineering, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran;4. Active Pharmaceutical Ingredients Research (APIRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran;1. School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China;2. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;3. Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA 92868, USA |
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| Abstract: | Novel chalcone-dithiocarbamate hybrids were designed, synthesized and evaluated for antiproliferative activity against selected cancer cell lines (MGC803, MCF7, and PC3). Among these analogues, (E)-2-oxo-2-((4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)amino)ethyl-4-(2-hydroxyethyl)piperazine-1-carbodithioate (12d) showed the best inhibitory activity against PC3 cells (IC50 = 1.05 μM). Cellular mechanism studies elucidated 12d could inhibit colony formation, arrest cell cycle at G2/M phase and induce DNA damage against PC3 cells. Compound 12d also induced mitochondrial apoptosis by caspase activation, MMP decrease, ROS production and catalase (CAT) inhibition. Importantly, 12d inhibited epithelial-mesenchymal transition (EMT) process by regulating EMT-related proteins (E-cadherin, N-cadherin, Vimentin, MMP2, MMP9). These results indicated that 12d is a promising lead compound and deserves further investigation for prevention and treatment of human prostate cancer. |
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| Keywords: | Chalcone-dithiocarbamate Catalase DNA damage Apoptosis Epithelial-mesenchymal transition |
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