2-(2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl)acetic acid | 1452162-19-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 2-(2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl)acetic acid
• 英文别名: 2-[2-Oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl]acetic acid；2-[2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl]acetic acid
• CAS: 1452162-19-4
• 化学式: C₇H₇F₃O₅
• 分子量: 228.125
• InChiKey: UKFKNNODLBJSAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl)acetic acid 、 4-氟溴苄 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 1.0h， 以88%的产率得到4-fluorobenzyl 2-(2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl)acetate
  参考文献：
  名称：

  Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability

  摘要：

  The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.040
• 作为产物：
  描述：

  benzyl 5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enoate 在 吡啶 、 盐酸 、 palladium 10% on activated carbon 、 氢气 、 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 丙酮 、 苯 为溶剂， 反应 3.13h， 生成 2-(2-oxo-4-(trifluoromethyl)-1,3-dioxan-4-yl)acetic acid
  参考文献：
  名称：

  Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability

  摘要：

  The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.11.040

文献信息

• Prodrugs of Fluorinated Mevalonates to Inhibit the Mevalonate Pathway of Streptococcus pneumoniae
  申请人：Silverman Richard B.

  公开号：US20130245284A1

  公开（公告）日：2013-09-19

  Fluorinated prodrug compounds as can be used for selective streptococcal mevalonate pathway inhibition.
• US9150534B2
  申请人：——

  公开号：US9150534B2

  公开（公告）日：2015-10-06
• [EN] PRODRUGS OF FLUORINATED MEVALONATES TO INHIBIT THE MEVALONATE PATHWAY OF STREPTOCOCCUS PNEUMONIAE<br/>[FR] PROMÉDICAMENTS DE MÉVALONATES FLUORÉS POUR INHIBER LA VOIE DU MÉVALONATE DU PNEUMOCOQUE
  申请人：UNIV NORTHWESTERN

  公开号：WO2013130792A2

  公开（公告）日：2013-09-06

  Fluorinated prodrug compounds as can be used for selective streptococcal mevalonate pathway inhibition.
• Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability
  作者：Soosung Kang、Mizuki Watanabe、J.C. Jacobs、Masaya Yamaguchi、Samira Dahesh、Victor Nizet、Thomas S. Leyh、Richard B. Silverman

  DOI：10.1016/j.ejmech.2014.11.040

  日期：2015.1

  The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates. (C) 2014 Elsevier Masson SAS. All rights reserved.