Design,synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents |
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| Institution: | 1. Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 12311, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;1. College of Life Science and Bioengineering & Beijing Key Laboratory of Environmental and Oncology, Beijing University of Technology, Beijing 100124, China;2. Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China;3. Guangxi Key Laboratory Cultivation Base for Polysaccharide Materials and Modifications, School of Marine Science and Biotechnology, Guangxi University for Nationalities, Nanning 530008, China;1. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt;3. Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt;4. Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;5. Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt;6. National Center for Natural Products Research, University of Mississippi, MS 38677, USA;7. Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt;8. Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA;9. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, 11884 Cairo, Egypt;10. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University – Egypt, International Costal Road, New Damietta, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt;3. National Center for Natural Products Research, University of Mississippi, MS 38677, USA;4. Pharmacognosy Department, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt;5. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;6. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;7. Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt;1. College of Life Science and Bioengineering & Beijing Key Laboratory of Environmental and Oncology, Beijing University of Technology, Beijing, 100124, China;2. Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China;3. Guangxi Key Laboratory Cultivation Base for Polysaccharide Materials and Modifications, School of Marine Sciences and Biotechnology, Guangxi University for Nationalities, Nanning, 530008, China;1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;2. Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China |
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| Abstract: | Different series of novel thieno 2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors. |
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| Keywords: | Antitumor VEGFR-2 Kinase inhibitors Cytotoxic effect ADMET Molecular modeling Cell cycle Caspase-3 induction |
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