title: A structure-activity relationship study of 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues on anti-thymidine phosphorylase and associated anti-angiogenic activities.
abstract: Thirty-three 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues were designed and synthesized which contained different substituents at meta- and/or para-positions of 2-phenyl or 2-benzyl ring attached to the fused ring structure. The preliminary pharmacological evaluation demonstrated that the 5-thioxo analogues of 1,2,4-triazolo[1,5-a][1,3,5]triazine exhibited a varying degree of inhibitory activity towards thymidine phosphorylase, comparable or better than reference compound, 7-Deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). Moreover, compounds 5q and 6i displayed a mixed-type of inhibitory mechanism in the presence of variable concentrations of thymidine (dThd). In addition, selected compounds were found to have a noticeable inhibitory effect on the expression of angiogenesis markers, including VEGF and MMP-9 in MDA-MB-231 breast cancer cells.
authors.affiliation: Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad 500090, Andhra Pradesh, India; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: hriday.bera@gmail.com.
authors.forename: Hriday
authors.initials: H
authors.lastname: Bera
authors.forename: Bee Jen
authors.initials: BJ
authors.lastname: Tan
authors.forename: Lingyi
authors.initials: L
authors.lastname: Sun
authors.forename: Anton V
authors.initials: AV
authors.lastname: Dolzhenko
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
authors.forename: Gigi Nagar Chee
authors.initials: GN
authors.lastname: Chiu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
chemical_list: C587513:1,2,4-triazolo(1,5-a)(1,3,5)triazin-5,7-dione; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D014227:Triazines; D014230:Triazoles; D042442:Vascular Endothelial Growth Factors; D013939:Thymidine Phosphorylase; D020780:Matrix Metalloproteinase 9
keywords: 1,2,4-Triazolo[1,5-a][1,3,5]triazine; Anti-angiogenesis; Breast cancer; HEEUTQZCYUHGBE-UHFFFAOYSA-N; KVEUPOJZRTUXSE-UHFFFAOYSA-N; Mixed-type inhibition; NDFXXVAZVMLCPA-UHFFFAOYSA-N; SAR; Thymidine phosphorylase inhibitors