title: Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II.
abstract: In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.
authors.affiliation: Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad 500090, India; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: hriday.bera1@gmail.com.
authors.forename: Hriday
authors.initials: H
authors.lastname: Bera
authors.affiliation: Jadavpur University, Kolkata 700032, India.
authors.forename: Probir kumar
authors.initials: Pk
authors.lastname: Ojha
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Bee Jen
authors.initials: BJ
authors.lastname: Tan
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore; School of Pharmacy, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Selangor, WA 46150, Malaysia.
authors.forename: Anton V
authors.initials: AV
authors.lastname: Dolzhenko
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phacwk@nus.edu.sg.
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Gigi Ngar Chee
authors.initials: GN
authors.lastname: Chiu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008958:Models, Molecular; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013457:Sulfur Compounds; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; D013939:Thymidine Phosphorylase; D020780:Matrix Metalloproteinase 9
keywords: Antiangiogenesis; Breast cancer; Mixed-type inhibition; Pyrazolo[1,5-a][1,3,5]triazine; Thymidine phosphorylase inhibitors