Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
PLoS One. 2019 Nov 19;14(11):e0225056. doi: 10.1371/journal.pone.0225056. eCollection 2019.
Natural flora is the richest source of novel therapeutic agents due to their immense chemical diversity and novel biological properties. In this regard, eighteen natural products belonging to different chemical classes were evaluated for their thymidine phosphorylase (TP) inhibitory activity. TP shares identity with an angiogenic protein platelet derived endothelial cell growth factor (PD-ECGF). It assists tumor angiogenesis and is a key player in cancer progression, thus an ideal target to develop anti-angiogenic drugs. Eleven compounds 1-2, 5-10, 11, 15, and 18 showed a good to weak TP inhibitory activity (IC50 values between 44.0 to 420.3 μM), as compared to standards i.e. tipiracil (IC50 = 0.014 ± 0.002 μM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 μM). Kinetic studies were also performed on active compounds, in order to deduce the mechanism of ligand binding to enzyme. To get further insight into receptor protein (enzyme) and ligand interaction at atomic level, in- sillico studies were also performed. Active compounds were finally evaluated for cytotoxicity test against mouse fibroblast (3T3) cell line. Compound 18 (Masoprocol) showed a significant TP inhibitory activity (IC50 = 44.0 ± 0.5 μM). Kinetic studies showed that it inhibits the enzyme in a competitive manner (Ki = 25.6 ± 0.008 μM), while it adopts a binding pose different than the substrate thymidine. It is further found to be non-toxic in MTT cytotoxicity assay. This is the first report on TP inhibitory activity of several natural compounds, some of which may serve as leads for further research towards drug the development.
天然植物群是新型治疗剂最丰富的来源，因为它们具有巨大的化学多样性和新颖的生物特性。在这方面，评估了属于不同化学类别的 18 种天然产物对胸苷磷酸化酶 (TP) 的抑制活性。TP 与血管生成蛋白血小板衍生的内皮细胞生长因子 (PD-ECGF) 具有相同的特性。它有助于肿瘤血管生成，是癌症进展的关键因素，因此是开发抗血管生成药物的理想靶点。与标准品替比拉西（IC50 = 0.014 ± 0.002 μM）和 7-脱氮嘌呤（IC50 = 41.0 ± 1.63 μM）相比，11 种化合物 1-2、5-10、11、15 和 18 显示出良好到弱的 TP 抑制活性（IC50 值在 44.0 到 420.3 μM 之间）。还对活性化合物进行了动力学研究，以推断配体与酶结合的机制。为了更深入地了解受体蛋白（酶）和配体在原子水平上的相互作用，还进行了计算机模拟研究。最后，对活性化合物进行了针对小鼠成纤维细胞（3T3）细胞系的细胞毒性试验。化合物 18（马索罗醇）表现出显著的 TP 抑制活性（IC50 = 44.0 ± 0.5 μM）。动力学研究表明，它以竞争性方式抑制酶（Ki = 25.6 ± 0.008 μM），同时采用与底物胸苷不同的结合构象。在 MTT 细胞毒性测定中进一步发现它没有毒性。这是首次报道几种天然化合物对 TP 的抑制活性，其中一些可能作为进一步研究开发药物的先导化合物。
