Synthesis,antiproliferative and pro-apoptotic activity of 2-phenylindoles |
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| Institution: | 1. School of Pharmacy & Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland;2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland;1. Institute of Molecular Physics, Polish Academy of Sciences, M. Smoluchowskiego 17, 60-179 Poznań, Poland;2. Department of Chemistry, Texas A&M University, College Station, TX 77842-3012, USA;3. Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université Rennes 1, Campus de Beaulieu, 35042 Rennes, France;1. University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia;2. University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Microbial Molecular Genetics and Ecology, Vojvode Stepe 444a, P.P. Box 23, 11010 Belgrade, Serbia;3. University of Belgrade, Faculty of Medicine, National Reference Medical Mycology Laboratory, Institute of Microbiology and Immunology, Dr Subotica 1, 11000 Belgrade, Serbia;1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;3. Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China;1. Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain;2. Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain;3. Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain;4. Centro de Investigación de Enfermedades Tropicales de La Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain;1. School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China;2. Department of Urology, University of California, Irvine, Orange, CA 92868, USA;3. The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China;4. School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, China |
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| Abstract: | Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50 values of 2.71 μM and 1.86 μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86. |
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| Keywords: | Phenylindoles Estrogen receptor Apoptosis Breast cancer Combretastatin |
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