Design,synthesis, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers |
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| Institution: | 1. Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt;2. Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt;3. Pharmaceutical Chemistry Department, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia;4. Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt;5. Faculty of Science and Arts, Mohail Asser, King Khalid University, Saudi Arabia;6. Zology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11284, Egypt;1. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy;2. Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States;3. Institute of Molecular Biology and Pathology (IBPM), CNR Consiglio Nazionale Delle Ricerche, C/o Sapienza University of Rome, Via Degli Apuli 4, I-00185 Roma, Italy;4. Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico Della Basilicata, Via Padre Pio 1, I-85028, Rionero in Vulture, Italy;5. Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy;6. Experimental Therapeutics IFOM-the FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy;7. APHAD, Via Della Resistenza 65, 20090 Buccinasco MI, Italy;1. Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;2. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;1. Department of Chemistry, Annamalai University, Annmalainagar 608 002, India;2. Department of Studies and Physics, University of Mysore, Managangothri, India;1. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 2014, Saudi Arabia;2. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;5. College of Medicine, Al-Rayyan Colleges, Al Madinah Al Munawarah, 41411, Saudi Arabia;6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;7. Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt;8. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Aljouf University, Aljouf, Sakaka, 2014, Saudi Arabia;9. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524, Sohag, Egypt;10. School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen, AB243UE, Ireland;1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University, Yantai, 264005, PR China;3. State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong;4. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK |
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| Abstract: | Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a–e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5′-(morpholinosulfonyl) spiro chromene-2, 3′-indolin]-2′-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo2,3–b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, 1H NMR, 13C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC50 values less than 10 µM. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32–19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC50 values are from 0.019 to 0.026 µM while IC50 of Lapatinib is 0.028 µM. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives. |
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| Keywords: | Isatin 3-Phenacylidene-2-indolinone Spirooxindoles |
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