Novel nalidixic acid derivatives targeting topoisomerase II enzyme; Design,synthesis, anticancer activity and effect on cell cycle profile |
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| Institution: | 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University In Cairo BUC, Cairo, Egypt;1. Basic Science Department, Higher Technological Institute, 10th Ramadan City, 228, Egypt;2. University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia 11566, Cairo, Egypt;3. University of Ain Shams, Faculty of Science, Department of Zoology, Abbassia 11566, Cairo, Egypt;1. College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea;2. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea;3. College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea;4. Department of Emergency Medical Technology, Daejeon University, Daejeon 300-716, Republic of Korea;1. Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan;2. Hyogo Prefectural Kobe High School, 1-5-1 Shironoshita-dori Nada-ku Kobe, Hyogo 657-0804, Japan;1. Academy of Advanced Interdisciplinary Studies, Qilu University of Technology (Shandong Academy of Sciences), Jinan, PR China;2. School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, PR China;3. Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China;4. State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology (Shandong Academy of Sciences), Jinan, PR China;1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China;2. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang, China;3. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, Jiangxi, China;4. School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China (UESTC), Chengdu 610054, Sichuan, China;5. The Affiliated Cangnan Hospital, Wenzhou Medical University, Cangnan 325800, Zhejiang, China;1. Department for Life Quality Studies, Alma Mater Studiorum-Università di Bologna, Corso D’Augusto 237, 47921, Rimini, Italy;2. Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy;3. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo, 5, 35131, Padova, Italy;4. Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125, Torino, Italy;5. Department of Industrial Chemistry “Toso Montanari”, Alma Mater Studiorum-Università di Bologna, Viale Del Risorgimento, 4, 40136, Bologna, Italy;6. Cell Death Investigation and Therapy Laboratory, Department of Human Structure and Repair, Ghent University, 9000, Ghent, Belgium;7. Cancer Research Institute Ghent, 9000, Ghent, Belgium;8. Department of Pathophysiology, Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia;9. Department of Biomolecular Sciences, Campus Scientifico “E. Mattei”, University of Urbino Carlo Bo, Via Ca’ Le Suore 2, Urbino, Italy |
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| Abstract: | AimDesign and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim.Materials & methodsAll the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC50 determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity.ResultsCompound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC50 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIβ inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC50 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg2+, hydrogen bonding with Asp 545 and arene cation interaction with His 759. |
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| Keywords: | Nalidixic acid Synthesis Design Anticancer activity Topoisomerase II enzyme Cell cycle analysis Apoptosis |
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