Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors |
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| Institution: | 1. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Istanbul University, Istanbul, Turkey;2. Department of Chemical Engineering, Bogazici University, Bebek, 34342, Istanbul, Turkey;3. 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;4. Faculty of Pharmacy, Istanbul Yeni Yuzyil University, Istanbul, Turkey;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. Chongqing Institute of Engineering, Chongqing, 400056, China;2. The Institute of Infection and Inflammation, China Three Gorges University, Yichang, Hubei, 443000, China;3. The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, 157000, China;4. Department of Surgery, Zhuji Affiliated Hospital of Shaoxing University, Zhejiang Province, 311800, China;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;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;3. Department of Pharmaceutical Technology in Process Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India;4. CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Uppal, Hyderabad 500007, India;1. Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand;2. Program in Applied Biological Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand;3. National Omics Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand;4. Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand;5. Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand;6. Center of Excellence on Environmental Health and Toxicology (EHT), Commission on Higher Education (CHE), Ministry of Education, Bangkok 10400, Thailand |
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| Abstract: | A new series of N’-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 μM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents. |
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| Keywords: | Anticancer activity Indole-2-carbohydrazides Thiazolidinyl-indole Tubulin polymerization Molecular docking |
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