Exploring new chemical functionalities to improve aromatase inhibition of steroids |
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| Institution: | 1. Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;2. UCIBIO.REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;3. CNC.IBILI, Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Portugal;4. Laboratorio di Chimica Farmaceutica, Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy;5. CNC.IBILI, University of Coimbra, Portugal;1. Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy;2. Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Cagliari, Italy;3. Dipartimento di Scienze della Salute, Università Magna Graecia di Catanzaro, Campus “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy;4. Department of Organic Chemistry, Semmelweis University, Hogyes Endre utca 7, H-1092 Budapest, Hungary;1. Dipartimento di Scienze Della Salute, Università“Magna Græcia” di Catanzaro, Campus Universitario “S. Venuta”, Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy;2. Net4Science Srl, Spin-off Accademico, Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy;3. CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade Do Porto, Porto, 4169-007, Portugal;4. UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade Do Porto, 4050-313, Porto, Portugal;5. Dipartimento di Medicina Clinica e Sperimentale, Università“Magna Græcia” di Catanzaro, Campus Universitario “S. Venuta”, Viale Europa, Loc. Germaneto, 88100, Catanzaro, Italy;6. Departamento Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, España, Spain;7. Instituto de Ciencias Químicas Aplicadas, Universidad Autonoma de Chile, Av. Libertador Bernardo O’Higgins, 7500912, Santiago de Chile, Chile;1. Dipartimento di Scienze della Salute, “Magna Græcia” University of Catanzaro, Campus “S. Venuta”, Viale Europa, Germaneto, 88100, Catanzaro, Italy;2. Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Università; degli Studi di Firenze, Sesto Fiorentino, Florence, Italy;3. Department of Pharmacy, University “Federico II” of Naples, Via D. Montesano, 49 I-80131, Naples, Italy;4. Department of Experimental and Clinical Medicine, “Magna Græcia” University of Catanzaro, Campus “S. Venuta”, Viale Europa, Germaneto, 88100, Catanzaro, Italy;5. Dipartimento di Chimica e Tecnologie chimiche, Università della Calabria, Via Pietro Bucci, 87036, Arcavacata di Rende, Cosenza, Italy;6. Net4Science Academic Spin-Off, “Magna Græcia” University of Catanzaro, Campus “S. Venuta”, Viale Europa, Germaneto, 88100, Catanzaro, Italy;1. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;2. Dipartimento di Scienze della Salute, “Magna Graecia” University of Catanzaro, Campus Universitario “S. Venuta”, Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy;3. Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;4. Istituto di Metodologie Chimiche, Laboratorio di Risonanza Magnetica “Annalaura Segre”, CNR, via Salaria km 29.300, 00015 Monterotondo, Rome, Italy;1. Department of Health Science, Catanzaro, Italy;2. Department of Experimental and Clinical Medicine, Catanzaro, Italy;3. Net4Science Academic Spin-Off, “Magna Græcia” University, Campus “Salvatore Venuta”, Catanzaro, Italy;4. College of Science and Technology, Temple University, Philadelphia, PA, USA |
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| Abstract: | In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure–activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50 = 0.11 μM), and the Δ9–11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 = 0.25 μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors. |
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| Keywords: | Steroids Aromatase inhibitors Synthesis Structure–activity relationships Induced-fit docking Molecular modeling |
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