Design,synthesis, and bioactivity of dihydropyrimidine derivatives as kinesin spindle protein inhibitors |
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| Institution: | 1. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China;2. The National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Nanchang 330006, China;3. Basic Medical College, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China;4. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China;5. College of Pharmacy, Hubei University of Science and Technology, Xianning 437100, China;1. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Chemistry, NED University of Engineering & Technology, Karachi 75270, Pakistan;4. Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan 23200, Pakistan;5. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia;1. Department of Chemistry, Hazara University, Mansehra 21120, Pakistan;2. Kulliyyah of Science, International Islamic University Malaysia, Bandar Indera Mahkota, 25200 Kuantan, Malaysia;3. Research Center for Modeling and Simulations (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan;4. Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA;5. Department of Pharmacy, University of Lahore, Defence Road Campus, Lahore 53700, Pakistan;6. Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;7. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;1. Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;3. Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada;1. Centre for Nanoscience & Nanotechnology, Panjab University, Chandigarh 160014, India;2. Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar 140001, Punjab, India;3. Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;4. Division of Biological Science and Technology, Yonsei University, Wonju 220-710, Republic of Korea;5. Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea;1. Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (UKZN), Westville, Durban 4001, South Africa;2. Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK |
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| Abstract: | A series of twenty-one 3,4-dihydropyrimidine derivatives bearing the heterocyclic 1,3-benzodioxole at position 4 in addition to different substituents at positions 2, 3 and 5 were designed and synthesized as monastrol analogs. The novel synthesized compounds were screened for their cytotoxic activity towards 60 cancer cell lines according to NCI (USA) protocol. Compounds 10b and 15 showed the best antitumor activity against most cell lines. Compound 15 was subsequently tested in 5-doses mode and displayed high selectivity towards CNS, prostate and leukemia subpanel with selectivity ratios of 22.30, 15.38 and 12.56, respectively at GI50 level. The IC50 of compounds 9d, 10b, 12, 15 and 16 against kinesin enzyme were 3.86 ± 0.12, 10.70 ± 0.35, 3.95 ± 0.12, 4.36 ± 0.14, and 14.07 ± 0.45 μM respectively, while the prototype compound, monastrol, reported IC50 value of 20 ± 0.42 μM. The safest compound among test compounds against normal cell line (HEK 293) is 10b with IC50 value of 62.02 ± 2.42 µM/ml in comparison to doxorubicin (IC50 = 11.34 ± 0.44 µM/ml). Cell cycle analysis of SNB-75 cells treated with compound 15 showed cell cycle arrest at G2/M phase. Further, the assay of levels of active caspase-3 and caspase-9 was investigated. Moreover, Molecular docking of compounds, 9d, 10b, 12, 15, 16, monastrol and mon-97 was performed to study the interaction between inhibitors and the kinesin spindle protein allosteric binding site. |
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| Keywords: | Dihydropyrimidine Kinesin spindle protein Cell cycle analysis Apoptosis Molecular docking |
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