trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs,ACS Medicinal Chemistry Letters

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trans-Fluorine Effect in Cyclopropane: Diastereoselective Synthesis of Fluorocyclopropyl Cabozantinib Analogs
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-11 , DOI: 10.1021/acsmedchemlett.0c00220
Janis Veliks ₁ , Melita Videja _{1,

2} , Artis Kinens ₁ , Raitis Bobrovs ₁ , Martins Priede ₁ , Janis Kuka ₁

Affiliation

Investigation of the trans-fluorine effect on the hydrolysis rate of diethyl 2-fluorocyclopropane-1,1-dicarboxylate provides synthetic access to both diastereomers of the fluorocyclopropyl analog of cabozantinib, a c-Met and VEGFR-2 inhibitor used as a first-line treatment for thyroid cancer and as a second-line treatment for renal cell carcinoma. Despite some known potent examples, there are only a few drug molecules that contain fluorocyclopropane moieties. Herein, we present a case study in which the monofluoro analog of a known cyclopropane-containing drug molecule displays an improved in vitro profile compared to the parent nonfluorinated structure. The fluorocyclopropane moiety may offer valuable fine-tuning options for lead optimization in drug discovery.

中文翻译：

环丙烷中的反式氟效应：氟环丙基卡博替尼类似物的非对映选择性合成

研究反式氟对 2-氟环丙烷-1,1-二羧酸二乙酯水解速率的影响，为合成卡博替尼的氟环丙基类似物的两种非对映异构体提供了途径，卡博替尼是一种 c-Met 和 VEGFR-2 抑制剂，用作一线甲状腺癌的治疗和肾细胞癌的二线治疗。尽管有一些已知的有效例子，但只有少数药物分子含有氟环丙烷部分。在此，我们提出了一个案例研究，其中与母体非氟化结构相比，已知的含环丙烷药物分子的单氟类似物显示出更好的体外特征。氟环丙烷部分可能为药物发现中的先导优化提供有价值的微调选项。

更新日期：2020-11-12

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