Structural investigation on thiazolo[5,4-d]pyrimidines to obtain dual-acting blockers of CD73 and adenosine A2A receptor as potential antitumor agents |
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| Institution: | 1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy;2. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy;3. Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1V 4G2, Canada;4. Département de Microbiologie-Infectiologie et d''Immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada;5. Departamento de Bioquimica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, MG, Brazil;1. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore, Pakistan;2. Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan;3. Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan;4. Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia;5. Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia;6. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC G1V 4G2, Canada;7. Département de microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada;8. Department of Chemistry, University of Sahiwal, Sahiwal 57000, Pakistan;1. Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Italy;2. Istituto di Fisica Applicata, CNR, Via Madonna del Piano 10, Sesto Fiorentino 50019, Florence, Italy;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Italy;4. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy;1. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;2. Department of Chemistry, Quaid-I-Azam University, 45320 Islamabad, Pakistan;3. Département de microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada;4. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC, Canada;1. Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy;2. Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy;1. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan;2. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan;3. Département de Microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada;4. Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada;5. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan;1. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India;2. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany |
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| Abstract: | Adenosine pathway, including its generating enzyme (CD73) and its receptors represents a key target for cancer immunotherapy. Here we aimed to search for novel compounds able to co-target the CD73 and the A2A adenosine receptor (A2A AR) as dual-blockers of adenosine generation and activity. The design project was to combine in the same molecule the thiazolo5,4-d]pyrimidine core, an essential pharmacophoric feature to block the A2A AR, with a benzenesulfonamide group which is a characteristic group of CD73 inhibitors. Most of the reported compounds resulted in inverse agonists of the human (h) A2A AR endowed with high affinity, selectivity and potency. However they were weak inhibitors of CD73 enzyme. Nevertheless, this study can be considered as a starting point to develop more active compounds. |
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| Keywords: | Thiazolo[5 4-d]pyrimidine CD73 inhibitors Cancer immunotherapy Antitumor agents |
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