Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.

Yano S; Kazuno H; Sato T; Suzuki N; Emura T; Wierzba K; Yamashita J; Tada Y; Yamada Y; Fukushima M; Asao T

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Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.

机译：6-亚甲基桥接的尿嘧啶衍生物的合成和评价。第2部分：人胸苷磷酸化酶抑制剂的优化及其对尿苷磷酸化酶的选择性。

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A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory activity was also evaluated. Compound 2 (TPI) has been selected for clinical evaluation based on its strong TP inhibition and excellent modulation of 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd) pharmacokinetics. As a result, TAS-102 (a combination of F(3)dThd and TPI) is currently in phase 1 clinical studies.

机译：已经优化了一系列新型的6-亚甲基桥接的尿嘧啶衍生物，以作为人胸苷磷酸化酶（TP）的抑制剂用于临床。我们描述它们的综合和评估。与以前报道的抑制剂1相比，胍基或an基的引入增强了TP的体外抑制活性。还评估了它们基于尿苷磷酸化酶抑制活性对TP的选择性。化合物2（TPI）由于其强大的TP抑制作用和2'-脱氧-5-（三氟甲基）尿苷（F（3）dThd）药代动力学的出色调节作用，已被选择用于临床评估。结果，TAS-102（F（3）dThd和TPI的组合）目前处于1期临床研究中。

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《Bioorganic and medicinal chemistry》 |2004年第13期|共8页
作者
Yano S; Kazuno H; Sato T; Suzuki N; Emura T; Wierzba K; Yamashita J; Tada Y; Yamada Y; Fukushima M; Asao T;
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正文语种 eng
中图分类基础医学;
关键词
tissue polypeptide specific antigen; Evaluation; inhibitors; derivatives;

机译：组织多肽特异性抗原;评估;抑制剂;衍生物;

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1. Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase. [J] . Yano S, Kazuno H, Sato T, Bioorganic and medicinal chemistry . 2004,第13期

机译：6-亚甲基桥接的尿嘧啶衍生物的合成和评价。第2部分：人胸苷磷酸化酶抑制剂的优化及其对尿苷磷酸化酶的选择性。
2. Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: Discovery of novel orally active inhibitors of human thymidine phosphorylase. [J] . Yano S, Kazuno H, Suzuki N, Bioorganic and medicinal chemistry . 2004,第13期

机译：6-亚甲基桥接的尿嘧啶衍生物的合成和评价。第1部分：发现人类胸苷磷酸化酶的新型口服活性抑制剂。
3. Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: Discovery of novel orally active inhibitors of human thymidine phosphorylase. [J] . Yano S, Kazuno H, Suzuki N, Bioorganic and Medicinal Chemistry . 2004,第13期

机译：6-亚甲基桥接的尿嘧啶衍生物的合成和评价。第1部分：发现人类胸苷磷酸化酶的新型口服活性抑制剂。
4. Purine Nucleoside Phosphorylase. Transition State Structure, Transition State Inhibitors and One-Third-The-Sites Reactivity [C] . Robert W. Miles, Peter C. Tyler Richard H. Furneaux~+, Carey K. Bagdassarian, Steenbock Symposium on Enzymatic Mechanisms . 1999

机译：嘌呤核苷磷酸化酶。过渡状态结构，过渡状态抑制剂和三分之一的场地反应性
5. I:- Design, synthesis and study of nucleotide prodrugs. II:- Synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU) and study of its mechanism of action as a thymidine phosphorylase inhibitor. III:- Design and synthesis of novel nucleotide analogs as alternative substrates for studying the mechanism of the thymidylate synthase-catalyzed reaction. [D] . Jain, Harsh Vardhan. 2010

机译：I：-核苷酸前药的设计，合成和研究。 II：5-氟-6-[（（2-氨基咪唑-1-基）甲基]尿嘧啶（AIFU）的合成及其作为胸苷磷酸化酶抑制剂的作用机理的研究。 III：-设计和合成新型核苷酸类似物作为研究底物胸苷酸合酶催化反应机理的替代底物。
6. SYNTHESIS AND IN VITRO EVALUATION OF 5-FLUORO-6-(2-IMINOPYRROLIDIN-1-YL)METHYLURACIL TPI(F): AN INHIBITOR OF HUMAN THYMIDINE PHOSPHORYLASE (TP) [O] . John R. Grierson, J. Scott Brockenbrough, Janet S. Rasey, -1

机译：5-氟-6 - （2- inminopyrlidin-1-基）甲基 UracilTPI（F）的合成和体外评价：人胸苷磷酸化酶（TP）的抑制剂
7. Synthesis, modeling and evaluation of 3'-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3'-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors [O] . Van Poecke Sara, Negri Ana, Janssens Jolien, 2011

机译：3'-（1-芳基-1H-四唑-5-基氨基）-取代的3'-脱氧胸苷衍生物作为有效和选择性的人线粒体胸苷激酶抑制剂的合成，建模和评估
8. Selective Killing of Human Malignant Cell Lines Deficient in Methylthioadenosine Phosphorylase, a Purine Metabolic Enzyme [R] . Kamatani, N., Nelson-Rees, W. A., Carson, D. A. 1981

机译：选择性杀死人类恶性细胞系缺乏甲基硫腺苷磷酸化酶，一种嘌呤代谢酶

Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.

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