Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 67, Issue -, Pages 325-334Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.06.051
Keywords
1,2,4-Triazolo[1,5-a][1,3,5]triazine; Thymidine phosphorylase inhibitors; SAR; Mixed-type inhibition; Breast cancer; Anti-angiogenesis
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Funding
- National Medical Research Council, Singapore [R-148-000-102-275]
- Academic Research Funds of National University of Singapore
- Gokaraju Rangaraju Educational Society
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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 mu M). 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. (C) 2013 Elsevier Masson SAS. All rights reserved.
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