3-[1-(3-amino-propyl)-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester | 786704-31-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3-[1-(3-amino-propyl)-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester
• 英文别名: methyl 3-aminopropyl-N-Teoc-histidinate；3-[1-(3-amino-propyl)-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-propionylamino)-propionic acid methyl ester；methyl (2S)-3-[1-(3-aminopropyl)imidazol-4-yl]-2-(2-trimethylsilylethoxycarbonylamino)propanoate
• CAS: 786704-31-2
• 化学式: C₁₆H₃₀N₄O₄Si
• 分子量: 370.524
• InChiKey: LMRIPDAFCBYYLE-AWEZNQCLSA-N

物化性质

• 沸点：
  537.8±50.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.38
• 重原子数：
  25
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[1-(3-amino-propyl)-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester 在 四丁基氟化铵 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.25h， 生成 (2S)-3-[1-[3-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]propyl]imidazol-4-yl]-2-aminopropanoic acid
  参考文献：
  名称：

  Conjugation of a novel histidine derivative to biomolecules and labelling with [99mTc(OH2)3(CO)3]+Electronic supplementary information (ESI) available: complete 1H and 13C NMR spectra of 14, 15, 16 and 19. See http://www.rsc.org/suppdata/ob/b4/b405575f/

  摘要：

  新的组氨酸衍生物3-{1-[3-(9H-芴-9-基甲氧基羧酰氨基)-丙基]-1H-咪唑-4-基}-2-(3-三甲基硅基-乙基氨基羧酸)-丙酸甲酯（7）通过将组氨酸尿素衍生物(7S)-5,6,7,8-四氢-7-(甲氧基羧基)-5-氧代咪唑-[1,5-c]-嘧啶（2）与Fmoc保护的3-碘丙胺进行烷基化，然后使用2-三甲基硅基乙醇开环反应制备而成。在使用HNEt2去除Fmoc后，将组氨酸胺衍生物通过酰胺形成与生物素、五肽亮氨酸-脑啡肽以及维生素B12-β-酸偶联，采用TBTU作为耦合试剂。为了使组氨酸能够进行标记，teoc保护基团通过NBu4F（用于生物素偶联物）或TFA（用于脑啡肽和B12偶联物）去除。将10−4 M浓度的生物偶联物与[99mTc(H2O)3(CO)3]+在50 °C下反应30分钟，在每个情况下HPLC放射色谱图中产生一个单一的新峰，确认了相应生物分子的定量标记。为了评估标记化合物的性质，还合成了与Re(CO)3的铼类似物，类似的滞留时间确认了与99mTc标记偶联物的身份。

  DOI：

  10.1039/b405575f
• 作为产物：
  描述：

  S-(+)-7-Methoxycarbonyl-5,6,7,8-tetrahydroimidazo<1,5-c>pyrimidin-5-on 在 二乙胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 125.0h， 生成 3-[1-(3-amino-propyl)-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester
  参考文献：
  名称：

  Conjugation of a novel histidine derivative to biomolecules and labelling with [99mTc(OH2)3(CO)3]+Electronic supplementary information (ESI) available: complete 1H and 13C NMR spectra of 14, 15, 16 and 19. See http://www.rsc.org/suppdata/ob/b4/b405575f/

  摘要：

  新的组氨酸衍生物3-{1-[3-(9H-芴-9-基甲氧基羧酰氨基)-丙基]-1H-咪唑-4-基}-2-(3-三甲基硅基-乙基氨基羧酸)-丙酸甲酯（7）通过将组氨酸尿素衍生物(7S)-5,6,7,8-四氢-7-(甲氧基羧基)-5-氧代咪唑-[1,5-c]-嘧啶（2）与Fmoc保护的3-碘丙胺进行烷基化，然后使用2-三甲基硅基乙醇开环反应制备而成。在使用HNEt2去除Fmoc后，将组氨酸胺衍生物通过酰胺形成与生物素、五肽亮氨酸-脑啡肽以及维生素B12-β-酸偶联，采用TBTU作为耦合试剂。为了使组氨酸能够进行标记，teoc保护基团通过NBu4F（用于生物素偶联物）或TFA（用于脑啡肽和B12偶联物）去除。将10−4 M浓度的生物偶联物与[99mTc(H2O)3(CO)3]+在50 °C下反应30分钟，在每个情况下HPLC放射色谱图中产生一个单一的新峰，确认了相应生物分子的定量标记。为了评估标记化合物的性质，还合成了与Re(CO)3的铼类似物，类似的滞留时间确认了与99mTc标记偶联物的身份。

  DOI：

  10.1039/b405575f

文献信息

• "N and/or nalpha derivatized, metal and organic protected l-histidine for coupling to biomolecules for highly efficient labeling with [m(oh2)3 (co)3]+ by fac coordination"
  申请人：Alberto Roger

  公开号：US20070077195A1

  公开（公告）日：2007-04-05

  The present invention relates to novel histidine derivatives that can be used for the labeling of biomolecules with radioactive metal tricarbonyls. The new derivatives have a histidine that is derivatized at the N ε and at least protected at the N α and optionally at the N δ ; or derivatized at the N α and at least protected at the N α and optionally at the N δ ; or derivatized at the N ε and N α and at least protected at the N α and optionally at the N δ ; or derivatized at the N ε ; or derivatized at the N α ; or derivatized at the N ε and N α ; or at least protected at the N α and optionally at the N δ .

  该发明涉及一种新型组氨酸衍生物，可用于将生物分子与放射性金属三羰基进行标记。这些新衍生物具有一个在Nε处衍生化的组氨酸，并且至少在Nα处受保护，可选地在Nδ处受保护；或者在Nα处衍生化，并且至少在Nα处受保护，可选地在Nδ处受保护；或者在Nε和Nα处衍生化，并且至少在Nα处受保护，可选地在Nδ处受保护；或者在Nε处衍生化；或者在Nα处衍生化；或者在Nε和Nα处衍生化；或者至少在Nα处受保护，可选地在Nδ处受保护。
• [EN] COBALAMINE DERIVATIVES USEFUL FOR DIAGNOSIS AND TREATMENT OF ABNORMAL CELLULAR PROLIFERATION<br/>[FR] DERIVES DE LA COBALAMINE SERVANT AU DIAGNOSTIC ET AU TRAITEMENT DE LA PROLIFERATION CELLULAIRE ANORMALE
  申请人：SOLIDAGO AG

  公开号：WO2005061527A1

  公开（公告）日：2005-07-07

  The invention relates to cobalamin derivatives (a) having no binding affinity or low binding affinity to the transport protein transcobalamin II TCII) and (b) retaining activity as a vitamin B12 substitute, optionally carrying a therapeutic and/or diagnostic agent, such as a radioactive metal. These compounds have a much reduced accumulation rate in blood and benign organs, such as kidney and liver, compared to the accumulation rate in neoplastic tissues, and are more rapidly eliminated from blood. The invention further relates to a method of diagnosis and a method of treatment of a neoplastic disease or an infection by microorganisms in a mammal comprising (a) exposing the mammal to a period of a vitamin B12 - free diet, and (b) subsequently applying a cobalamin derivative of the invention carrying a diagnostic and/or therapeutic agent. By selecting cobalamin derivatives acting as vitamin B12 substitutes, the risk of the formation of resistant off­spring in neoplastic tissue is much reduced.

  该发明涉及一种钴胺衍生物（a），其与运输蛋白转钴胺II（TCII）无结合亲和力或低结合亲和力，并且（b）保留维生素B12替代物的活性，可选地携带治疗和/或诊断剂，如放射性金属。与在恶性组织中的积累速率相比，这些化合物在血液和良性器官（如肾脏和肝脏）中的积累速率大大降低，并且更快地从血液中排出。该发明还涉及一种诊断方法和治疗方法，用于治疗哺乳动物中的恶性疾病或由微生物感染引起的感染，包括（a）使哺乳动物暴露于维生素B12 - 无食物的饮食期间，以及（b）随后应用携带该发明的钴胺衍生物的诊断和/或治疗剂。通过选择作为维生素B12替代物的钴胺衍生物，大大降低了恶性组织中抵抗性后代形成的风险。
• Conjugates of vitamin B12 with Nε-functionalized histidine for labeling with [99mTc(OH2)3(CO)3]+: synthesis and biodistribution studies in tumor bearing mice
  作者：Dave R. van Staveren、Robert Waibel、Stefan Mundwiler、P. August Schubiger、Roger Alberto

  DOI：10.1016/j.jorganchem.2004.09.050

  日期：2004.12

  In this work, histidine derivatives bearing an acetic acid or a propyl amine substituent on the N-epsilon-atom are conjugated to the b-acid, c-acid and d-acid moiety of cyanocobalamin (vitamin B12) via amide formation. Four different derivatives were prepared with different sites of conjugation (b-, c- or d-acid) and different spacer lengths between histidine and the acid moiety. These conjugates can be efficiently labeled with [Tc-99m(OH2)(3)(CO)(3)](+) at yields higher than 95% under mild conditions (50degreesC, 30 min, 10(-4) M). The biodistribution of the Tc-99m(CO)(3) labeled conjugates is determined in mice bearing B16-F10 melanoma tumors. The organ distribution varies significantly for each of the derivatives with the percentage injected dose per gram of tumor tissue ranging from 4.4 +/- 0.9 to 9.2 +/- 2.0. (C) 2004 Elsevier B.V. All rights reserved.
• Conjugation of a novel histidine derivative to biomolecules and labelling with [99mTc(OH2)3(CO)3]+Electronic supplementary information (ESI) available: complete 1H and 13C NMR spectra of 14, 15, 16 and 19. See http://www.rsc.org/suppdata/ob/b4/b405575f/
  作者：Dave R. van Staveren、Stefan Mundwiler、Ulrich Hoffmanns、Jae Kyoung Pak、Bernhard Spingler、Nils Metzler-Nolte、Roger Alberto

  DOI：10.1039/b405575f

  日期：——

  The new histidine derivative 3-1-[3-(9H-fluoren-9-ylmethoxycarbonylamino)-propyl]-1H-imidazol-4-yl}-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester (7) has been prepared via alkylation of the histidine urea derivative (7S)-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo-[1,5-c]-pyrimidine (2) with Fmoc-protected 3-iodopropyl-amine, followed by ring opening with 2-trimethylsilylethanol. After Fmoc cleavage by HNEt2, the histidine amine derivative was coupled to biotin, to the pentapeptide leucine-enkephalin and to Vitamin B12-b-acid by amide formation, employing TBTU as the coupling reagent. In order to make the histidine accessible for labelling, the teoc protecting group was removed by either NBu4F (for the biotin conjugate) or by TFA (for the enkephalin and B12 conjugates). Reaction of a 10−4 M solution of the bioconjugates with [99mTc(H2O)3(CO)3]+ at 50 °C for 30 min led to the formation of one single new peak in the HPLC radiochromatogram in each case, confirming quantitative labelling of the respective biomolecules. To assess the nature of the labelled compounds, the rhenium analogues with Re(CO)3 were also synthesised and similar retention times confirmed the identity with the 99mTc labelled conjugates.

  新的组氨酸衍生物3-1-[3-(9H-芴-9-基甲氧基羧酰氨基)-丙基]-1H-咪唑-4-基}-2-(3-三甲基硅基-乙基氨基羧酸)-丙酸甲酯（7）通过将组氨酸尿素衍生物(7S)-5,6,7,8-四氢-7-(甲氧基羧基)-5-氧代咪唑-[1,5-c]-嘧啶（2）与Fmoc保护的3-碘丙胺进行烷基化，然后使用2-三甲基硅基乙醇开环反应制备而成。在使用HNEt2去除Fmoc后，将组氨酸胺衍生物通过酰胺形成与生物素、五肽亮氨酸-脑啡肽以及维生素B12-β-酸偶联，采用TBTU作为耦合试剂。为了使组氨酸能够进行标记，teoc保护基团通过NBu4F（用于生物素偶联物）或TFA（用于脑啡肽和B12偶联物）去除。将10−4 M浓度的生物偶联物与[99mTc(H2O)3(CO)3]+在50 °C下反应30分钟，在每个情况下HPLC放射色谱图中产生一个单一的新峰，确认了相应生物分子的定量标记。为了评估标记化合物的性质，还合成了与Re(CO)3的铼类似物，类似的滞留时间确认了与99mTc标记偶联物的身份。