title: Thymidine esters as substrate analogue inhibitors of angiogenic enzyme thymidine phosphorylase in vitro.
abstract: Thymidine phosphorylase (TP) catalyzes the cleavage of thymidine into thymine and 2-deoxy-α-d-ribose-1-phosphate. Elevated activity of TP prevents apoptosis, and induces angiogenesis which ultimately leads to tumor growth and metastasis. Critical role of TP in cancer progression makes it a valid target in anti-cancer research. Discovery of small molecules as TP inhibitors is vigorously pursued in cancer therapy. In the present study, we functionalized thymidine as benzoyl ester to synthesize compounds 3-16. In vitro evaluation of thymidine esters for their thymidine phosphorylase inhibition activity was subsequently carried out. Compounds 4, 10, 14, and 15 showed good activities with lower IC50values than the standard, 7-deazaxanthine (IC50=41.0±1.63μM). Among them, compound 14 showed five folds higher activity (IC50=7.5±0.8μM), while 4 (IC50=18.5±1.0μM) and 10 (IC50=18.8±1.2μM) showed two folds higher activity than the standard. Compound 15 showed slightly better activity (IC50=33.3±1.5μM) to the standard. Potent compounds were further subjected to kinetic and molecular docking studies to identify their mode of inhibition, and to study their interactions with the protein at atomic level, respectively. All active compounds were non-cytotoxic to mouse fibroblast 3T3 cell line. These results identify thymidine esters as substrate analogue (substrate-like) inhibitors of angiogenic enzyme thymidine phosphorylase for further studies.
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sumaira
authors.initials: S
authors.lastname: Javaid
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Marium
authors.initials: M
authors.lastname: Ishtiaq
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muniza
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: abdul.hameed@iccs.edu.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21412, Saudi Arabia. Electronic address: hej@cyber.net.pk.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D016475:3T3 Cells; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C115661:7-deazaxanthine; D004791:Enzyme Inhibitors; D004952:Esters; D014970:Xanthines; D013939:Thymidine Phosphorylase; D013936:Thymidine
keywords: Angiogenic enzyme; Substrate-analogue inhibitors; Thymidine esters; Thymidine phosphorylase inhibition