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首页> 外文期刊>Journal of Medicinal Chemistry >Novel prodrugs of tegafur that display improved anticancer activity and Antiangiogenic properties
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Novel prodrugs of tegafur that display improved anticancer activity and Antiangiogenic properties

机译：替加福的新型前药显示出改善的抗癌活性和抗血管生成特性

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摘要

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more, potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiocenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4(l H,3H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.
机译：描述了通过5-氟-1-（四氢-2-呋喃基）-2,4（1H，3H）-嘧啶二酮（tegafur，1）的羟甲基化或酰氧基甲基化衍生的5-氟尿嘧啶家族的新的和更有效的前药。抗氧化剂N-乙酰半胱氨酸减弱了丁酰氧基甲基-替加氟衍生物3的抗癌活性，而不是替加氟的抗癌活性，这表明前药活性的提高部分地由活性氧的增加介导。在体外基质胶测定中发现化合物3是比替加氟更有效的抗血管生成剂。在抑制小鼠异种移植物中的4T1乳腺癌肺转移和HT-29人结肠癌肿瘤生长方面，体内3明显比替加氟更有效。总之，替加福的多功能前药在体外和体内显示出对癌细胞的选择性，抗血管生成活性和抗癌活性，优于替加福。 5-FU-1-口服的前药5-氟-1-（四氢-2-呋喃基）-2,4（1 H，3H）-嘧啶二酮（tegafur，1）已被广泛用于治疗中度胃肠道恶性肿瘤功效。这项研究的目的是开发和表征由替加福的羟甲基化或酰氧基甲基化衍生的5-FU家族的新的和更有效的前药。比较替加氟和新前药对多种癌细胞系存活力的影响，结果表明，新前药的IC50和IC90值比替加福低5-10倍。尽管在敏感的HT-29和耐药的LS-1034结肠癌细胞系之间观察到了替加福的IC50值之间存在显着差异，但前药对它们的影响程度相似，表明它们克服了耐药性。前药效力的增加可归因于甲醛和丁酸在代谢降解时释放的抗增殖作用。抗氧化剂N-乙酰半胱氨酸减弱了丁酰氧基甲基-替加氟衍生物3的抗癌活性，而不是替加氟的抗癌活性，这表明前药活性的提高部分地由活性氧的增加介导。发现在体外基质胶测定中的化合物3比替加氟更有效的抗血管生成剂。在抑制小鼠异种移植物中的4T1乳腺癌肺转移和HT-29人结肠癌肿瘤生长方面，体内3明显比替加氟更有效。总之，替加氟的多功能前药在体外和体内显示出对癌细胞的选择性，抗血管生成活性和抗癌活性，优于替加氟。

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