Design,synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors |
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| Institution: | 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt;2. Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Ti-Qar, Iraq;3. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA;2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., SGM 628, Boston, MA 02115, USA;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District) Cairo, Egypt;4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566 Cairo, Egypt;1. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi 832002, China;2. School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China;3. College of Pharmacy, Harbin Medical University, Harbin 150081, China;1. Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya 11566, Cairo, Egypt;2. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Riyadh, Saudi Arabia;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt;1. Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), PO box 29, Nasr City, Cairo, Egypt;2. Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt;3. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States |
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| Abstract: | Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo1,5-a]1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug. |
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| Keywords: | CDK2 inhibitors Anticancer Purine bioisostere Docking |
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