Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents |
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Affiliation: | 1. Euromed Research Center, Euromed Institute of Technology, Euromed University of Fes (UEMF)–Route de Meknès, 30000 Fes, Morocco;2. Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759, Orléans cedex 2 54067, France;3. Institut de Chimie des Substances Naturelles, CNRS, Université Paris-Saclay, Gif-sur-Yvette, France;1. Department of Pharmacy, Zhengzhou Railway Vocational & Technical College, Zhengzhou 450018, China;2. Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, 45, rue des Saints Peres, 75006 Paris, France;3. CQM – Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal;4. Glycovax Pharma, 424 Guy Street, Suite 202, Montréal, QC, H3J 1S6, Canada;5. School of Materials Science and Engineering/Center for Nano Energy Materials, Northwestern Polytechnical University, Xi’an 710072, China;6. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China;7. Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain;8. Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas, ISCIII, 28031 Madrid, Spain;9. Euromed Research Center, Euromed Faculty of Engineering, Euromed University of Fes (UEMF), Route de Meknès, 30000 Fès, Morocco;10. Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4 France;11. Université Toulouse 118 route de Narbonne, 31077 Toulouse Cedex 4, France;1. Department of Chemistry, The Oxford College of Engineering, Bangalore (Karnataka) -560068, India;2. Department of Chemistry, Regional Ayurveda Research Institute for Drug Development, Gwalior (M.P.) – 474009, India;3. Department of Biotechnology, Lovely Professional University, Jalandhar (Punjab) – 144111, India;4. Regional Advanced Water Testing Laboratory, Mohali (Punjab) -160059, India;5. Punjab Biotechnology Incubators, Mohali (Punjab) -160059, India;1. Academy of Integrative Medicine, College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, Dalian 116044, China;2. Institute of Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, China;3. School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China;4. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Ganjingzi District, Linggong Road No.2, Dalian 116024, China;1. Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea;2. University of Science and Technology in Korea, 217 Gajeongro, Daejeon 34113, Republic of Korea;3. Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro Daejeon 34141, Republic of Korea;1. Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, Goiânia, GO, Brazil;2. Ciências Exatas e Tecnológicas, Universidade Estadual de Goiás, Anápolis, GO, Brazil;3. Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brazil |
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Abstract: | A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC50 values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker’s best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8. |
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Keywords: | Ethacrynic acid Sulfonamides Anti-cancer Anti-proliferative Cancer cells Safety ratios |
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