Reigan Philip, Gbaj Abdul, Stratford Ian J, Bryce Richard A, Freeman Sally
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Eur J Med Chem. 2008 Jun;43(6):1248-60. doi: 10.1016/j.ejmech.2007.07.015. Epub 2007 Aug 6.
Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure.
胸苷磷酸化酶（TP）在多种肿瘤类型中过度表达，在肿瘤血管生成、生长、侵袭和转移中起重要作用。TP的酶活性是其血管生成作用所必需的，因此，TP抑制剂在癌症化疗中具有重要意义。已经设计并合成了一系列已知TP抑制剂的黄嘌呤氧化酶（XO）激活前药，其最终目的是改善肿瘤选择性和药代动力学特性。这些前药不是TP抑制剂，但在尿嘧啶环部分的C-2和/或C-4处被XO选择性氧化，以生成所需的TP抑制剂。TP抑制剂和XO激活前药的分子模型使其在人TP晶体结构的活性位点中的结合合理化。
