Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.
Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.
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DOI：
10.1002/cmdc.201600496
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发表时间：
2016-12-06
期刊：
影响因子：
3.4
通讯作者：
Gütschow M
中科院分区：
文献类型：
--
作者：
Ambrożak A;Steinebach C;Gardner ER;Beedie SL;Schnakenburg G;Figg WD;Gütschow M
新型沙利度胺衍生物作为免疫调节剂和抗血管生成剂的开发在过去二十年中已经复苏。在这里，我们报告的设计和合成三种化学型的巴比妥酸衍生的沙利度胺结构：邻苯二甲酰亚胺，四氟邻苯二甲酰亚胺，和四氟苯甲酰氨基巴比妥酸。后者是通过一个新的串联反应，包括开环和脱羧的氟活化的邻氨基甲酸中间体。通过测量大鼠主动脉环外植体中微血管生长的减少，在离体测定中评价了三种化学型的三十种化合物的抗血管生成特性。四氟邻苯二甲酰亚氨基巴比妥酸中的邻苯二甲酰亚胺部分的四氟化是必不可少的，因为所有的非氟化对应物都失去了抗血管生成活性。在相应的四氟苯甲酰胺巴比妥酸的情况下，五元环的开放和伴随的构象自由度增加，耐受性良好。它们的活性被保留，尽管它们的分子结构在扭转柔性和可能的氢键网络方面不同，如比较X射线晶体学分析所揭示的。
The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses.
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影响因子：
5.7
作者：
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