(S)-(3-bromo-4,5-dihydroisoxazol-5-yl)methanamine | 143005-79-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑啉类
• 英文名称: (S)-(3-bromo-4,5-dihydroisoxazol-5-yl)methanamine
• 英文别名: [(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]methanamine
• CAS: 143005-79-2
• 化学式: C₄H₇BrN₂O
• 分子量: 179.016
• InChiKey: JLOLOZBWSBAUHW-VKHMYHEASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  8
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-苄氧羰基-L-酪氨酸 、 (S)-(3-bromo-4,5-dihydroisoxazol-5-yl)methanamine 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以76%的产率得到benzyl (S)-1-(((S)-3-bromo-4,5-dihydroisoxazol-5-yl)methylamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-ylcarbamate
  参考文献：
  名称：

  Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

  摘要：

  Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.

  DOI：

  10.1021/jm060839a
• 作为产物：
  描述：

  (3-bromo-4,5-dihydroisoxazol-5-yl)methanamine 在 扁桃酸 作用下， 以 甲醇 、 异丙醇 为溶剂， 反应 16.0h， 以87%的产率得到(S)-(3-bromo-4,5-dihydroisoxazol-5-yl)methanamine
  参考文献：
  名称：

  In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model

  摘要：

  蛋白质交联酶组织转谷氨酰胺酶（TG2；EC 2.3.2.13）与包括癌症在内的多种疾病的发病机制有关。最近，我们报道了两种高潜力放射性标记不可逆 TG2 抑制剂的合成和初步评估。本研究进一步评估了这两种化合物在乳腺癌（MDA-MB-231）肿瘤异种移植模型中对体内活性组织转谷氨酰胺酶的成像。[11C]1和[18F]2在SCID小鼠体内的代谢稳定性与之前报道的在Wistar大鼠体内的稳定性相当。对 MDA-MB-231 细胞和分离的肿瘤进行的实时定量聚合酶链反应分析表明，TG2 的表达量很高，而其他转谷氨酰胺酶的表达量很低。PET 成像显示，肿瘤对[11C]1 的摄取量较低（40-60 分钟后每克约为注射剂量的 0.5%（%ID/g）），且洗脱相对较快。随着时间的推移，肿瘤对[18F]2的摄取量在稳步上升（40-60 分钟后约为 1.7 %ID/g）。用 TG2 抑制剂 ERW1041E 对动物进行预处理可降低肿瘤活性浓度，而使用未标记的 2 则可增强这种抑制作用。 在该模型中，[11C]1 的 TG2 靶向潜力似乎不足，而使用 [18F]2 则可实现 TG2 靶向。因此，[18F]2 可用于未来的研究，以明确活性组织转谷氨酰胺酶在疾病中的作用。

  DOI：

  10.1186/s13550-018-0388-2

文献信息

• [EN] MODULATION OF TISSUE TRANSGLUTAMINASE ACTIVATION IN DISEASE<br/>[FR] MODULATION DE L'ACTIVATION DE LA TRANSGLUTAMINASE TISSULAIRE DANS UNE MALADIE
  申请人：UNIV LELAND STANFORD JUNIOR

  公开号：WO2015116846A1

  公开（公告）日：2015-08-06

  Compositions and methods are provided for modulating the physiological activation of tissue transglutaminase (TG2); which methods can include inhibiting the activity of TG2 associated with inflammatory disorders, which disorders may include, without limitation, sepsis, ischemic reperfusion injury, renal fibrosis, and the like.

  提供了调节组织转谷氨酰胺酶（TG2）生理活化的组合物和方法；这些方法可以包括抑制与炎症性疾病相关的TG2活性，这些疾病可能包括但不限于败血症、缺血再灌注损伤、肾脏纤维化等。
• Development of Rhodesain Inhibitors with a 3-Bromoisoxazoline Warhead
  作者：Roberta Ettari、Lucia Tamborini、Ilenia C. Angelo、Silvana Grasso、Tanja Schirmeister、Leonardo Lo Presti、Carlo De Micheli、Andrea Pinto、Paola Conti

  DOI：10.1002/cmdc.201300390

  日期：2013.12

  Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3‐bromoisoxazoline warhead with a specific peptidomimetic recognition moiety. All derivatives behaved as inhibitors of rhodesain, with low micromolar Ki values. Their activity against the enzyme was found to be paralleled by an in vitro antitrypanosomal activity, with IC50 values in the mid‐micromolar range. Notably, a preference

  通过将对映体纯的3-溴异恶唑啉战斗部与特定的拟肽识别部分相结合，可获得新型的罗德萨因抑制剂。所有衍生物均表现为罗得沙星的抑制剂，其微摩尔K i值低。发现它们对酶的活性与体外抗锥虫活性平行，IC 50值在中微摩尔范围内。值得注意的是，观察到寄生虫优于人蛋白酶，特别是组织蛋白酶B和L。
• Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors
  作者：Roberta Ettari、Santo Previti、Sandro Cosconati、Jochen Kesselring、Tanja Schirmeister、Silvana Grasso、Maria Zappalà

  DOI：10.3109/14756366.2015.1108972

  日期：2016.11.1

  Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3-bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety. All compounds were proven to inhibit rhodesain with Ki values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC50 values ranging from the mid-micromolar

  通过将对映体纯的3-溴异恶唑啉战斗部与作为特定识别部分的1,4-苯并二氮杂sc骨架相结合，开发出了新型罗得沙因抑制剂。事实证明，所有化合物均能抑制罗得沙因，其Ki值在低微摩尔范围内。发现它们对罗德沙因的活性与体外抗锥虫活性有关，IC50值范围从最活跃的罗德沙因抑制剂（R，S，S）-3的中微摩尔值到低微摩尔值。由于所有化合物均被证明是人组织蛋白酶L的弱抑制剂，因此所有化合物均对目标酶具有良好的选择性。
• Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2
  作者：Cornelius Klöck、Zachary Herrera、Megan Albertelli、Chaitan Khosla

  DOI：10.1021/jm501145a

  日期：2014.11.13

  Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.
• Bromonitrile oxide [3+2] cycloadditions in water
  作者：John C. Rohloff、James Robinson、John O. Gardner

  DOI：10.1016/s0040-4039(00)79827-3

  日期：1992.5

  Bromonitrite oxide can be generated homogeneously in water at acidic pH, allowing efficient [3 + 2] cycloaddition with water soluble olefins and acetylenes. Allylammonium salts react with high regioselectivity and without the need for N-group protection.