Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors |
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| Affiliation: | 1. Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, TX 78712, USA;2. Department of Chemistry, The University of Texas at Austin, TX 78712, USA;3. Graduate Program in Cell and Molecular Biology, The University of Texas at Austin, TX 78712, USA;4. Department of Biomedical Engineering, Cockrell School of Engineering, College of Engineering, The University of Texas at Austin, TX 78712, USA;1. Department of Chemical Sciences, Tezpur University (A Central University), Tezpur, Napaam 784028, Assam, India;2. Department of Chemistry, Rajiv Gandhi University (A Central University), Rono Hills, Doimukh 791112, Arunachal Pradesh, India;3. Department of Chemistry, Indian Institute of Technology, Guwahati 781039, Assam, India;4. Department of Molecular Biology and Biotechnology, Tezpur University (A Central University), Tezpur, Napaam 784028, Assam, India;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;3. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;4. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;5. Department of Pharmacology and Toxicology, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt;6. Department of Biology, School of Science and Engineering (SSE), American University in Cairo, New Cairo, P.O. Box 11835, Egypt;1. Department of Chemistry and Biochemistry, The City College of New York, New York, New York, USA;2. Macromolecular Crystallization Facility, CUNY ASRC, New York, New York, USA;3. Division of Chemical Biology and Medicinal Chemistry, The University of Texas, Austin, Texas, USA;4. Interdisciplinary Life Sciences Graduate Program, The University of Texas, Austin, Texas, USA;5. PhD Program in Biochemistry, The Graduate Center of CUNY, New York, New York, USA;6. PhD Program in Chemistry, The Graduate Center of CUNY, New York, New York, USA;7. PhD Program in Physics, The Graduate Center of CUNY, New York, New York, USA |
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| Abstract: | A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6–16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R1, R2, and R3). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC50 = 420 nM) and 9 (IC50 = 930 nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-d-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors. |
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| Keywords: | Uracil eEF-2K inhibitor Kinase inhibitor Homology modeling |
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