H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.
Bioorg Chem. 2015 Dec;63:142-51. doi: 10.1016/j.bioorg.2015.10.006. Epub 2015 Oct 29.
Thymidine phosphorylase (TP) over expression plays an important role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. In this regard, a series of twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 were evaluated for thymidine phosphorylase inhibitory activity. Six compounds 5, 6, 20, 2, 23, and 3 were found to be active against thymidine phosphorylase enzyme with IC50 values in the range of 42.9-294.6μM. 7-Deazaxanthine (IC50=41.0±1.63μM) was used as a standard inhibitor. Compound 5 showed a significant activity (IC50=42.9±1.0μM), comparable to the standard. The enzyme kinetic studies on the most active compounds 5, 6, and 20 were performed for the determination of their modes of inhibition, and dissociation constants Ki. All active compounds were found to be largely non-cytotoxic against the mouse fibroblast 3T3 cell line. This study identifies a novel class of thymidine phosphorylase inhibitors which may be further investigated as leads to develop therapeutic agents.
胸苷磷酸化酶（TP）过表达在几种病理条件下起着重要作用，如类风湿关节炎、慢性炎症性疾病、银屑病和肿瘤血管生成。在这方面，评估了一系列 25 种 2-芳基喹唑啉-4(3H)-酮衍生物 1-25 的胸苷磷酸化酶抑制活性。发现 6 种化合物 5、6、20、2、23 和 3 对胸苷磷酸化酶酶具有活性，IC50 值在 42.9-294.6μM 范围内。7-脱氮嘌呤（IC50=41.0±1.63μM）用作标准抑制剂。化合物 5 表现出显著的活性（IC50=42.9±1.0μM），与标准相当。对最活性化合物 5、6 和 20 进行酶动力学研究，以确定它们的抑制模式和离解常数 Ki。所有活性化合物对小鼠成纤维细胞 3T3 细胞系的细胞毒性均不大。本研究鉴定了一类新型胸苷磷酸化酶抑制剂，可进一步作为开发治疗剂的先导化合物进行研究。
