N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)glycyrrhetinamide | 1334318-82-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)glycyrrhetinamide
• 英文别名: (2S,4aS,6aR,6aS,6bR,8aR,10S,12aS,14bR)-N-[2-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]ethyl]-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1H-picene-2-carboxamide
• CAS: 1334318-82-9
• 化学式: C₄₁H₅₅F₆N₃O₄
• 分子量: 767.896
• InChiKey: YVMOIVJQLNKUOE-LPVMKEIWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.6
• 重原子数：
  54
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  108
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  甘草次酸 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)glycyrrhetinamide
  参考文献：
  名称：

  [ 11 C]光气用于放射性合成N-（2- {3- [3,5-双（三氟甲基）]苯基[ 11 C]脲基}乙基）甘草次乙酰胺，它是肿瘤中蛋白酶体和激酶的抑制剂

  摘要：

  据报道，N-（2- {3- [3,5-双（三氟甲基）]苯基脲基}乙基）甘草次酸酰胺（2）是脲基取代的甘草次酸的衍生物（1），具有对蛋白酶体和蛋白酶体的有效抑制活性。激酶，在肿瘤中过表达。在这项研究中，我们使用[ 11 C]光气（[ 11 C] COCl 2）作为标记剂标记了这种不对称尿素2，期望[ 11 C] 2可以成为正体发射层析成像配体，用于蛋白酶体和核糖体的成像。肿瘤中的激酶。[ 11 C] 2的放射合成策略使3,5-双（三氟甲基）苯胺的盐酸盐（4 ·HCl）与[ 11 C] COCl 2反应，可能生成异氰酸酯[ 11 C] 6，然后使[ 11 C] 6与N-（ 2-氨基乙基）甘草次酸酰胺（3）。

  DOI：

  10.1016/j.bmcl.2012.04.049

文献信息

• Synthesis and plasma pharmacokinetics in CD-1 mice of a 18β-glycyrrhetinic acid derivative displaying anti-cancer activity
  作者：Benjamin Lallemand、Moustapha Ouedraogo、Nathalie Wauthoz、Touria Lamkami、Veronique Mathieu、Ivan Jabin、Karim Amighi、Robert Kiss、Jacques Dubois、Jonathan Goole

  DOI：10.1111/j.2042-7158.2012.01603.x

  日期：2013.1.29

  The plasma pharmacokinetic profile in CD-1 mice of a novel 18β-glycyrrhetinic acid (GA) derivative, which displays in vitro anti-cancer activity, was assessed.

  This study involved an original one-step synthesis of N-(2-3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide, (2) a compound that displays marked anti-proteasome and anti-kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight.

  Compound 2 displayed IC50  in vitro growth inhibitory concentrations of 29 and 8 μm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t1/2dist of ∼3 min) but slowly eliminated (t1/2elim = ∼77 min).

  This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti-kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration.

  评估一种新型18β-甘草酸（GA）衍生物在CD-1小鼠中的血浆药代动力学特征，该衍生物在体外显示抗癌活性。

  本研究涉及一种原始的N-(2-3-[3,5-双三氟甲基苯基]脲基}乙基)-甘草酸酰胺（2）的一步合成，该化合物显示出明显的抗蛋白酶和抗激酶活性。评估2在人正常NHDF成纤维细胞与人U373胶质母细胞瘤细胞上的生物选择性特征。在CD1小鼠中进行2的最大耐受剂量（MTD）分析，并使用40 mg/kg体重的急性静脉给药分析其血清药代动力学。

  化合物2在NHDF成纤维细胞和U373胶质母细胞瘤细胞上显示出IC50体外生长抑制浓度分别为29和8 μm，因此生物选择性指数约为4。静脉药代动力学参数显示，2迅速分布（t1/2dist约为3分钟），但缓慢消除（t1/2elim = 约77分钟）。

  本研究描述了一种原始可靠的GA衍生物纳米乳剂，具有抗蛋白酶和抗激酶特性，应进一步在体内使用各种人源异种移植物或小鼠同种肿瘤模型中进行单次和慢性静脉给药的测试。

• [EN] 18-BETA-GLYCYRRHETINIC ACID DERIVATIVES WITH ANTI-TUMOR ACTIVITY<br/>[FR] DÉRIVÉS D'ACIDE 18?-GLYCYRRHÉTINIQUE AYANT UNE ACTIVITÉ ANTITUMORALE
  申请人：UNIV BRUXELLES

  公开号：WO2012022780A1

  公开（公告）日：2012-02-23

  The invention relates to the medical and cosmetic field, more precisely the field of anticancer treatment and treatment of inflammatory diseases and diabetes and the field of anti-aging or anti-wrinkling agents using newly synthesized 18β-glycyrrhetinic acid derivatives and there use in the treatment of said disorders or symptoms.

  这项发明涉及医学和美容领域，更准确地说是抗癌治疗、炎症性疾病和糖尿病治疗以及抗衰老或抗皱剂领域，使用新合成的18β-甘草酸衍生物及其在治疗上述疾病或症状中的应用。
• <i>N</i>-(2-{3-[3,5-Bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (<b>6b</b>): A Novel Anticancer Glycyrrhetinic Acid Derivative that Targets the Proteasome and Displays Anti-Kinase Activity
  作者：Benjamin Lallemand、Fabien Chaix、Marina Bury、Céline Bruyère、Jean Ghostin、Jean-Paul Becker、Cédric Delporte、Michel Gelbcke、Véronique Mathieu、Jacques Dubois、Martine Prévost、Ivan Jabin、Robert Kiss

  DOI：10.1021/jm200285z

  日期：2011.10.13

  18-beta-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent compound, with IC50 in vitro growth inhibitory concentrations in single-digit micromolarity in a panel of 8 cancer cell lines. Compound 6b is cytostatic and displays similar efficiency in apoptosis-sensitive versus apoptosis-resistant cancer cell lines through, at least partly, the inhibition of the activity of a cluster of a dozen kinases that are implicated in cancer cell proliferation and in the control of the actin cytoskeleton organization. Compound 6b also inhibits the activity of the 3 proteolytic units of the proteasome. Compound 6b thus represents an interesting hit from which future compounds could be derived to improve chemotherapeutic regimens that aim to combat cancers associated with poor prognoses.
• Utilization of [11C]phosgene for radiosynthesis of N-(2-{3-[3,5-bis(trifluoromethyl)]phenyl[11C]ureido}ethyl)glycyrrhetinamide, an inhibitory agent for proteasome and kinase in tumors
  作者：Chiharu Asakawa、Masanao Ogawa、Masayuki Fujinaga、Katsushi Kumata、Lin Xie、Tomoteru Yamasaki、Joji Yui、Toshimitsu Fukumura、Ming-Rong Zhang

  DOI：10.1016/j.bmcl.2012.04.049

  日期：2012.6

  N-(2-3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for proteasome and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea 2 using [11C]phosgene ([11C]COCl2) as a labeling agent with the expectation that [11C]2 could become

  据报道，N-（2- 3- [3,5-双（三氟甲基）]苯基脲基}乙基）甘草次酸酰胺（2）是脲基取代的甘草次酸的衍生物（1），具有对蛋白酶体和蛋白酶体的有效抑制活性。激酶，在肿瘤中过表达。在这项研究中，我们使用[ 11 C]光气（[ 11 C] COCl 2）作为标记剂标记了这种不对称尿素2，期望[ 11 C] 2可以成为正体发射层析成像配体，用于蛋白酶体和核糖体的成像。肿瘤中的激酶。[ 11 C] 2的放射合成策略使3,5-双（三氟甲基）苯胺的盐酸盐（4 ·HCl）与[ 11 C] COCl 2反应，可能生成异氰酸酯[ 11 C] 6，然后使[ 11 C] 6与N-（ 2-氨基乙基）甘草次酸酰胺（3）。