Discovery of a novel DNA binding agent via design and synthesis of new thiazole hybrids and fused 1,2,4-triazines as potential antitumor agents: Computational,spectrometric and in silico studies |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;1. Department of Chemistry, Kurukshetra University, Kurukshetra, 136119, Haryana, India;2. Departamento de Química Orgánica y Bio-orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040, Madrid, Spain;3. School of Chemistry, Trinity College, Dublin, Dublin 2, Ireland;4. School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Dublin 2, Ireland;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt;3. Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt;1. National Institute of Science Technology and Development Studies New Delhi India;2. Department of Chemistry Kurukshetra University Kurukshetra-136119 Haryana, India;3. Department of Biochemistry University College Kurukshetra University Kurukshetra-136119 Haryana India;4. Department of Natural Sciences, University of Houston, Downtown, Houston, USA-77002;1. Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India;2. Academy of Scientific and Innovative Research, New Delhi 110 025, India;3. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India;4. School of Pharmaceutical Education and Research(SPER), Jamia Hamdard, New Delhi 110062, India;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;2. Organic Chemistry Department, National Organization For Drug & Control Research, Cairo, Egypt;3. Department of Applied Organic Chemistry, National Research Center, Dokki, P.O. Box 12622, Giza, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey;2. Department of Pharmaceutical Chemistry, School of Pharmacy, Medipol University, 34083 Istanbul, Turkey;3. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey |
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| Abstract: | New series of furan–thiazole hybrids (3a-f), thiazolo2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI50 MG-MID = 14.22 µM) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb+3) probe revealed increased fluroresence of DNA-3d-Tb+3 mixture due to damage of the double-stranded DNA. Also, UV–vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04 ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski’s rule. |
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| Keywords: | Thiazoles Fused 1 2 4-triazines Antitumor COMPARE Molecular Electrostatic Potential DNA binding Florescence detection UV–vis absorption Lipinski’s rule |
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