Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase
Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase
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DOI：
10.1016/s0006-2952(01)00783-3
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发表时间：
2001-11-01
影响因子：
5.8
通讯作者：
Schwartz, EL
中科院分区：
文献类型：
--
作者：
Klein, RS;Lenzi, M;Schwartz, EL
胸苷磷酸化酶 (TP) 催化胸苷和其他嘧啶 2'-脱氧核糖核苷的可逆磷酸解。此外，在许多体外和体内试验中，TP已被证明具有血管生成活性，并且其血管生成活性与其催化活性相关。合成了一系列5-和6-取代的尿嘧啶衍生物并评估了它们抑制TP活性的能力。其中最活跃的化合物是 6-氨基取代的尿嘧啶类似物 6-(2-氨基乙基)氨基-5-氯尿嘧啶 (AEAC)，它是一种竞争性抑制剂，K-i 为 165 nM。 AEAC 的抑制活性对 TP 具有选择性，因为它在浓度高达 1 mM 时不会抑制嘌呤核苷磷酸化酶或尿苷磷酸化酶。在改良的博伊登室体外试验中，人重组 TP 诱导人脐静脉内皮细胞 (HUVEC) 迁移，并且这种作用可以被 TP 抑制剂消除。抑制剂的作用对 TP 具有特异性，因为它们对血管内皮生长因子 (VEGF) 的趋化作用没有影响。当 TP 转染的人结肠癌和乳腺癌细胞代替纯化的血管生成因子在 Boyden 室测定中共培养时，也会诱导 HUVEC 迁移，并且 TP 抑制剂几乎完全阻断肿瘤细胞介导的迁移。这些研究表明，TP 抑制剂可能对依赖 TP 驱动的血管生成的病理状况有用。 (C) 2001 Elsevier Science Inc. 保留所有权利。
Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine and other pyrimidine 2'-deoxyribonucleosides. In addition, TP has been shown to possess angiogenic activity in a number of in vitro and in vivo assays, and its angiogenic activity has been linked to its catalytic activity. A series of 5- and 6-substituted uracil derivatives were synthesized and evaluated for their abilities to inhibit TP activity. Among the most active compounds was a 6-amino-substituted uracil analog, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), which was a competitive inhibitor with a K-i of 165 nM. The inhibitory activity of AEAC was selective for TP, as it did not inhibit purine nucleoside phosphorylase or uridine phosphorylase at concentrations up to 1 mM. Human recombinant TP induced human umbilical vein endothelial cell (HUVEC) migration in a modified Boyden chamber assay in vitro, and this action could be abrogated by the TP inhibitors. The actions of the inhibitors were specific for TP, as they had no effect on the chemotactic actions of vascular endothelial growth factor (VEGF). HUVEC migration was also induced when TP-transfected human colon and breast carcinoma cells were co-cultured in the Boyden chamber assay in place of the purified angiogenic factors, and a TP inhibitor blocked the tumor cell-mediated migration almost completely. These studies suggest that inhibitors of TP may be useful in pathological conditions that are dependent upon TP-driven angiogenesis. (C) 2001 Elsevier Science Inc. All rights reserved.