Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening |
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| Affiliation: | 1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152 – 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland;2. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152 – 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland;3. School of Biological and Health Sciences, Technology University Dublin, Dublin City Campus, Kevin St., Dublin 8 D08 NF82, Ireland;4. School of Chemistry, Trinity College Dublin, Dublin 2, Ireland;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;1. College of Chemistry, Beijing Normal University, Beijing 100875, PR China;2. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA;3. Five Eleven Pharma Inc., Philadelphia, PA 19104, USA;1. Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, Xiangyang 441053, PR China;2. State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, PR China;3. Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China;1. Departments of Pharmaceutical Sciences, University of California, Irvine, CA 92697-3900, United States;2. Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, United States;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;2. College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt;6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New giza, km 22, Cairo–Alexandria Desert Road, Cairo, Egypt;7. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea;8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;9. Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt;10. Department of Orthopedics and Traumatology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;11. Clinical Pharmacy Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia;12. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia |
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| Abstract: | 4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity). |
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| Keywords: | Estrogen receptor alpha Estrogen receptor beta Isoform selectivity Subtype selectivity Benzopyran Anticancer Anti-proliferative Breast cancer Cytotoxic Knovenagel condensation Molecular modeling EI" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" Electron Impact ER" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" Estrogen receptor GTP" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" Guanidine triphosphate HRMS" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" High Resolution Molecular Ion Determination IC" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" Inhibitory concentration IR" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," _" :" Infrared LDB" },{" #name" :" keyword" ," $" :{" id" :" k0130" }," $$" :[{" #name" :" text" ," _" :" Ligand binding domain LBP" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," _" :" Ligand binding Pocket LRMS" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," _" :" Low Resolution Mass Spectra MTD" },{" #name" :" keyword" ," $" :{" id" :" k0160" }," $$" :[{" #name" :" text" ," _" :" Maximum tolerated dose MTT" },{" #name" :" keyword" ," $" :{" id" :" k0170" }," $$" :[{" #name" :" text" ," _" :" 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide NMR" },{" #name" :" keyword" ," $" :{" id" :" k0180" }," $$" :[{" #name" :" text" ," _" :" Nuclear Magnetic Resonance ORTEP" },{" #name" :" keyword" ," $" :{" id" :" k0190" }," $$" :[{" #name" :" text" ," _" :" Oak Ridge Thermal Ellipsoid Plot PDB" },{" #name" :" keyword" ," $" :{" id" :" k0200" }," $$" :[{" #name" :" text" ," _" :" Protein Data Bank PBS" },{" #name" :" keyword" ," $" :{" id" :" k0210" }," $$" :[{" #name" :" text" ," _" :" Phosphate buffer saline SAR" },{" #name" :" keyword" ," $" :{" id" :" k0220" }," $$" :[{" #name" :" text" ," _" :" Structure-Activity Relationship SERM" },{" #name" :" keyword" ," $" :{" id" :" k0230" }," $$" :[{" #name" :" text" ," _" :" Selective Estrogen Receptor Modulation TBDMS" },{" #name" :" keyword" ," $" :{" id" :" k0240" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" tert" },{" #name" :" __text__" ," _" :" -Butyldimethylchlorosilane THF" },{" #name" :" keyword" ," $" :{" id" :" k0250" }," $$" :[{" #name" :" text" ," _" :" Tetrahydrofuran TLC" },{" #name" :" keyword" ," $" :{" id" :" k0260" }," $$" :[{" #name" :" text" ," _" :" Thin Layer Chromatography TMCS" },{" #name" :" keyword" ," $" :{" id" :" k0270" }," $$" :[{" #name" :" text" ," _" :" Trimethylchlorosilane TMS" },{" #name" :" keyword" ," $" :{" id" :" k0280" }," $$" :[{" #name" :" text" ," _" :" Tetramethylsilane |
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