Abstract
Over-expression of thymidine phosphorylase (TP) plays a key role in many pathological complications, including angiogenesis which leads to cancer cells proliferation. Thus in search of new anticancer agents, a series of 4-hydroxybenzohydrazides (1–29) was synthesized, and evaluated for in vitro thymidine phosphorylase inhibitory activity. Twenty compounds 1–3, 6–14, 16, 19, 22–24, and 27–29 showed potent to weak TP inhibitory activities with IC50 values in the range of 6.8 to 229.5 μM, in comparison to the standards i.e. tipiracil (IC50 = 0.014 ± 0.002 μM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 μM). Kinetic studies on selected inhibitors 3, 9, 14, 22, 27, and 29 revealed uncompetitive and non-competitive modes of inhibition. Molecular docking studies of these inhibitors indicated that they were able to interact with the amino acid residues present in allosteric site of TP, including Asp391, Arg388, and Leu389. Antiproliferative (cytotoxic) activities of active compounds were also evaluated against mouse fibroblast (3T3) and prostate cancer (PC3) cell lines. Compounds 1, 2, 19, and 22–24 exhibited anti-proliferative activities against PC3 cells with IC50 values between 6.5 to 10.5 μM, while they were largely non-cytotoxic to 3T3 (mouse fibroblast) cells proliferation. Present study thus identifies a new class of dual inhibitors of TP and cancer cell proliferation, which deserves to be further investigated for anti-cancer drug development.
Highlights
Thymidine phosphorylase (TP) (EC 2.4.2.4) is an enzyme of pyrimidine salvage pathway, primarily responsible for maintaining nucleotide homeostasis
Role of TP as angiogenic enzyme was proposed to be identical to human platelet derived endothelial cell growth factor (PD-ECGF), which promotes angiogenesis by facilitating endothelial cell proliferation, and migration [2]
We evaluated 4-hydroxylbenzohydarzide derivatives for their TP inhibitory activity (Fig 1)
Summary
Thymidine phosphorylase (TP) (EC 2.4.2.4) is an enzyme of pyrimidine salvage pathway, primarily responsible for maintaining nucleotide homeostasis. Over-expression of TP in tumor cell lines is an indication of its role in angiogenesis [1]. Role of TP as angiogenic enzyme was proposed to be identical to human platelet derived endothelial cell growth factor (PD-ECGF), which promotes angiogenesis by facilitating endothelial cell proliferation, and migration [2]. TP Enzyme is present in many cells and tissues, such as platelets, stromal cells, macrophages, endothelial cells, reticulocytes, glial cells, and ovary [1].
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