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Tyrosine kinase inhibition effects of novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines ligand: Synthesis,biological screening and molecular modeling studies
Institution:1. Deparment of Applied Organic Chemistry, National Research Centre, 12622 Dokki, Egypt;2. Department of Photochemistry, National Research Centre, 12622 Dokki, Egypt;3. Department of Green Chemistry, National Research Centre, 12622 Dokki, Egypt;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt;5. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt;6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt;7. National Cancer Institute, Chemotherapeutic Agents Repository, Fisher BioServices, Germantown, MD 20874, USA;1. Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;2. Bioinformatics Wing, Mycology & Plant Pathology Lab, Department of Botany, Osmania University, Hyderabad 500007, India;3. Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;4. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;1. Grupo/Semillero de Investigación en Compuestos Heterocíclicos, Universidad del Atlántico, Km 7 Vía Puerto Colombia, Barranquilla, Colombia;2. Grupo de Investigación en Fotoquímica y Fotobiología, Universidad del Atlántico, Km 7 Vía Puerto Colombia, Barranquilla, Colombia;3. Grupo de Fotodinámica Molecular, Universidad de los Andes, Carrera 1 No. 18A - 10, Bogotá, Colombia;4. Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, Av. Pedro de Valdivia 641, Santiago, Chile;5. Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071, Jaén, Spain;6. Grupo de Investigación de Compuestos Heterocíclicos, Universidad del Valle, Cali, Colombia;1. Department of Pharmaceutical Sciences, Rasthrasant Tukadoji Maharaj Nagpur University, Nagpur 440033, Maharashtra, India;2. Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), TATA Memorial Centre, Kharghar, Navi Mumbai 410 210, India;3. Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Kalabhavan Campus, Palace Road, Vadodara 390 001, Gujrat, India;1. Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France;2. Équipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco;1. Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;2. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;3. Bioengineering & Environmental Science, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;4. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India;1. School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran;2. Department of Medicinal Chemistry, Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;3. Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran;4. Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Nur, Mazandaran, Iran;5. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran;6. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran;7. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Abstract:Tyrosine kinases are one of the most critical mediators in the signaling path way. Late studies have proved the part of tyrosine kinases in the pathophysiology of cancer diseases. This current research paper has focused on investigating the novel Pyrazolo1,5-a]pyrimidines and Pyrido2,3-d]pyrimidines as a small molecules that can inhibit tyrosine kinase in cancer cells. NCI protocol was applied to test the antitumor activity of such compounds. Leukemia and renal cancer cell lines proved to be sensitive to some derivatives such as 6b–d, 9a and 11 with GI% values ranging from 30.4 to 41.3%. In addition, compound 11 proved to be the most active against MCF-7 with GI% 62.5. The synthesized compounds were also evaluated for their inhibitory effects against EGFR kinase enzyme. Compound 9b proved to be the most active one among the synthesized series with inhibition % value of 81.72 at 25 nM concentration and IC50 8.4 nM which is very close to the reference drug Sorafenib. In vitro cytotoxicity test was also performed using the MCF-7 breast cell line. Computer modeling using the active site of tyrosine kinase as a template and the most active tyrosine kinase inhibitors were calculated. Docking studies of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results.
Keywords:Synthesis  Anticancer evaluation  Tyrosine kinase inhibition  Molecular docking calculations
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