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J Med Chem. 2019 Feb 14;62(3):1231-1245. doi: 10.1021/acs.jmedchem.8b01305. Epub 2019 Jan 17.

Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer.

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Laboratório de Desenvolvimento e Controle de Qualidade em Medicamentos , Universidade Federal do Pampa , 97508-000 Uruguaiana , RS , Brazil.
Laboratório de Produtos Naturais e Sintéticos, Instituto de Biotecnologia , Universidade de Caxias do Sul , 95070-560 Caxias do Sul , RS , Brazil.


Overexpressed human thymidine phosphorylase (hTP) has been associated with cancer aggressiveness and poor prognosis by triggering proangiogenic and antiapoptotic signaling. Designed as transition-state analogues by mimicking the oxacarbenium ion, novel pyrimidine-2,4-diones were synthesized and evaluated as inhibitors of hTP activity. The most potent compound (8g) inhibited hTP in the submicromolar range with a noncompetitive inhibition mode with both thymidine and inorganic phosphate substrates. Furthermore, compound 8g was devoid of apparent toxicity to a panel of mammalian cells, showed no genotoxicity signals, and had low probability of drug-drug interactions and moderate in vitro metabolic rates. Finally, treatment with 8g (50 mg/(kg day)) for 2 weeks (5 days/week) significantly reduced tumor growth using an in vivo glioblastoma model. To the best of our knowledge, this active compound is the most potent in vitro hTP inhibitor with a kinetic profile that cannot be reversed by the accumulation of any enzyme substrates.

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