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.
J Med Chem. 2019 Feb 14;62(3):1231-1245. doi: 10.1021/acs.jmedchem.8b01305. Epub 2019 Jan 17.
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.
过表达的人胸腺嘧啶磷酸化酶（hTP）通过触发促血管生成和抗细胞凋亡信号与癌症侵袭性和不良预后相关。新型嘧啶-2,4-二酮类化合物被设计为过渡态类似物，通过模拟氧杂卡宾离子来模拟，被评估为 hTP 活性的抑制剂。最有效的化合物（8g）以亚微摩尔范围抑制 hTP，对胸苷和无机磷酸盐底物具有非竞争性抑制模式。此外，化合物 8g 对一系列哺乳动物细胞没有明显的毒性，没有遗传毒性信号，药物相互作用的可能性低，体外代谢率适中。最后，使用体内脑胶质瘤模型，8g（50 mg/（kg·天））治疗 2 周（每周 5 天）显著降低了肿瘤生长。据我们所知，这种活性化合物是最有效的体外 hTP 抑制剂，其动力学特征不能通过任何酶底物的积累来逆转。
