Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
Department of Pharmacology, Rawalpindi Medical University, Rawalpindi 463000, Pakistan.
Bioorg Chem. 2018 Oct;80:99-111. doi: 10.1016/j.bioorg.2018.05.026. Epub 2018 Jun 1.
Thymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC = 1.09 ± 0.004 μM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions.
胸苷磷酸化酶（TP）是一种血管生成酶。它在血管生成、肿瘤生长、侵袭和转移中起着重要作用。在目前的研究工作中，我们研究了二氢嘧啶-2-酮（DHPM-2-ones）结构修饰对 TP 抑制的影响。通过 C-6 位的结构修饰，设计并合成了一系列十八个 3,4-二氢嘧啶-2-酮的新衍生物。然后，所有这些新衍生物都被评估了对大肠杆菌胸苷磷酸化酶（TP）的体外抑制作用。恶二唑衍生物 4a-e 在低微摩尔浓度水平下表现出优异的 TP 抑制作用，优于标准药物 7-脱氮黄嘌呤（7-DX）。在所有这些化合物中，发现 4b 的抑制作用最强，IC = 1.09 ± 0.004 μM。代表性化合物的抗血管生成潜力也在鸡胚尿囊膜（CAM）试验中进行了研究。同样，化合物 4b 在 CAM 试验中被发现是一种有效的抗血管生成化合物。还使用分子操作环境（MOE）进行了对接研究，以进一步分析这些化合物的抑制模式。最活跃抑制剂的结合模式分析表明，尽管存在稳定的氢键和疏水相互作用，但这些抑制剂很好地适应了酶的结合位点。
