1-(9-amino-3-aza-2-oxononyl)-4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane | 866831-91-6

• 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: 1-(9-amino-3-aza-2-oxononyl)-4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
• 英文别名: tri-tert-butyl 2,2',2"-((10-(2-((6-aminohexyl)amino)-2-oxoethyl))-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate；DOTAMA(tBuO)3-C6-NH2；N-tert-butylDOTAMA-C6-NH2；DOTAMA(OtBu)3C6NH2；DOTA-tris(t-Bu)ester-C6-amine；tert-butyl 2-[4-[2-(6-aminohexylamino)-2-oxoethyl]-7,10-bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetate
• CAS: 866831-91-6
• 化学式: C₃₄H₆₆N₆O₇
• 分子量: 670.934
• InChiKey: WLXVNKPJOWTNIT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  47
• 可旋转键数：
  20
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  1-(9-amino-3-aza-2-oxononyl)-4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane 在 gadolinium(III) chloride 、 N,N-二异丙基乙胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 24.0h， 生成 1-[9-(1-adamantane)carbonylamino-3-aza-2-oxononyl]-1,4,7,10-tetraazacyclododecane-4,7,10-triacetate gadolinium
  参考文献：
  名称：

  γ1β8-环糊精低聚物的设计与合成：可能作为树枝状多载体应用的新平台

  摘要：

  我们报道了由八个β-环糊精（β-CD）单元组成的水溶性星状大分子平台的合成和表征，该平台通过双（三唑基）烷基间隔基锚定在γ-CD核的较窄边缘上。高效的合成规程基于微波（MW）促进的CD单叠氮化物与CD单乙炔的Cu催化的1,3-偶极环加成反应。通过弛豫滴定和核磁弛豫分散（NMRD）谱图评估了该构建体的配体承载能力，这表明它是良好的，这得到了分子动力学模拟的支持。为了证明获得具有高宿主能力的超分子结构的可行性，我们设计了一个二聚体平台，该平台是通过γ-CD核芯通过双（硫代胆酸）接头将两个九聚体连接在一起而形成的。考虑到潜在的生物学应用，评估了细胞毒性和与人血清白蛋白结合的程度。该树枝状多载体的性质使其适用于药物和诊断目的，范围从靶向药物递送到分子成像。

  DOI：

  10.1002/chem.201301215
• 作为产物：
  描述：

  N-苄氧羰基-1,6-二氨基己烷盐酸盐 在 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-(9-amino-3-aza-2-oxononyl)-4,7,10-tris(tert-butyloxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
  参考文献：
  名称：

  SIB-DOTA: A trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies

  摘要：

  A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [I-131]SIB-DOTA in 27.1 +/- 6.2% (n = 2) conjugation yields and its targeting properties to the same mAb labeled with [I-125]SGMIB both in vitro and in vivo using U87MG.Delta EGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [I-131]SIB-DOTA-L8A4 was 21.4 +/- 0.5% and 26.2 +/- 1.1% of initially bound radioactivity at 16 and 24 h, respectively. In comparison, these values for [I-125]SGMIB-L8A4 were 16.7 +/- 0.5% and 14.9 +/- 1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.10.025

文献信息

• Synthesis of a carborane-containing cholesterol derivative and evaluation as a potential dual agent for MRI/BNCT applications
  作者：Diego Alberti、Antonio Toppino、Simonetta Geninatti Crich、Chiara Meraldi、Cristina Prandi、Nicoletta Protti、Silva Bortolussi、Saverio Altieri、Silvio Aime、Annamaria Deagostino

  DOI：10.1039/c3ob42414f

  日期：——

  A new dual imaging and therapeutic agent is proposed to improve the efficacy of boron neutron capture therapy in cancer treatment.

  提出了一种新的双重成像和治疗剂，旨在提高硼中子俘获治疗在癌症治疗中的疗效。
• Tuning Glutamine Binding Modes in Gd-DOTA-Based Probes for an Improved MRI Visualization of Tumor Cells
  作者：Rachele Stefania、Lorenzo Tei、Alessandro Barge、Simonetta Geninatti Crich、Ibolya Szabo、Claudia Cabella、Giancarlo Cravotto、Silvio Aime

  DOI：10.1002/chem.200801567

  日期：2009.1

  hepatocarcinoma) and healthy rat hepatocytes has shown that the system containing the glutamine vector bound through the α‐carboxylic group displays a markedly higher affinity for tumor cells. The observed behavior is rationalized in terms of the exploitation of an additional glutamine transporter active in hepatic tumor cells.

  合成了三种靶向谷氨酰胺转运蛋白的新型磁共振成像探针。它们由一个Gd-DOTA-单酰胺部分（DOTA = 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）组成，它通过六个碳原子链连接到一个由谷氨酰胺残基结合的载体上通过α-羧基，γ-羧酰胺基或α-氨基官能团。HTC（大鼠肝癌）和健康的大鼠肝细胞对它们的摄取表明，含有通过α-羧基结合的谷氨酰胺载体的系统对肿瘤细胞的亲和力明显更高。通过利用在肝肿瘤细胞中有活性的其他谷氨酰胺转运蛋白，使观察到的行为合理化。
• Bifunctional ligands based on the DOTA-monoamide cage
  作者：Alessandro Barge、Lorenzo Tei、Dharita Upadhyaya、Franco Fedeli、Lorena Beltrami、Rachele Stefanìa、Silvio Aime、Giancarlo Cravotto

  DOI：10.1039/b715844k

  日期：——

  Efficient routes to DOTA-monoamide ligands bearing amino, hydroxyl, aldehyde and maleimido groups are described. These functional groups, which can be spaced at will from the coordination cage, will readily react with suitable groups of targeting moieties. Bioconjugates obtained in this way can be used for diagnostic imaging and therapeutic applications.

  本文介绍了获得带有氨基、羟基、醛基和马来酰亚胺基团的 DOTA-单酰胺配体的有效途径。这些官能团可随意与配位笼保持一定间距，很容易与合适的靶向基团发生反应。以这种方式获得的生物共轭物可用于诊断成像和治疗应用。
• Spectral Properties of Pro‐multimodal Imaging Agents Derived from a NIR Dye and a Metal Chelator
  作者：Zongren Zhang、Samuel Achilefu

  DOI：10.1562/2005-06-08-ra-568

  日期：2005.11

  Monomolecular multimodal imaging agents (MOMIAs) are able to provide complementary diagnostic information of a target diseased tissue. We developed a convenient solid‐phase approach to construct two pro‐MOMIAs (before incorporating radiometal) derived from 1,4,7,10‐tetraazacy‐clododecane‐1,4,7,10‐tetraacetic acid (DOTA) and cypate, a near‐infrared (NIR) fluorescent dye analogous to indocyanine green (ICG). The possible interaction between d orbitals of transition metal DOTA complexes or free metals and the p orbitals of cypate chromophore could quench the fluorescence of pro‐MOMIAs. However, we did not observe significant changes in the spectral properties of cypate upon conjugation with DOTA and subsequent chelation with metals. The fluorescence intensity of the chelated and nonmetal‐chelated PRO‐MOMIAs remained fairly the same in dilute 20% aqueous dimethylsulfoxide (DMSO) solution (1 × 10⁻⁶M). Significant reduction in the fluorescence intensity of pro‐MOMIAs occurred in the presence of a large excess of metal ions (> 1 molar ratio for indium and 20‐fold for a copper relative to pro‐MOMIA). This study suggests the feasibility of using MOMIAs for combined optical and radioisotope imaging.

  摘要分子多模态成像剂（MOMIAs）能够提供目标病变组织的互补诊断信息。我们开发了一种简便的固相方法来构建两种原 MOMIAs（在加入放射性金属之前），它们分别来自 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）和一种类似于吲哚菁绿（ICG）的近红外（NIR）荧光染料环酯。过渡金属 DOTA 复合物或游离金属的 d 轨道与环磷酸酯发色团的 p 轨道之间可能存在相互作用，这可能会淬灭原 MOMIAs 的荧光。然而，我们并没有观察到环磷酸酯与 DOTA 共轭以及随后与金属螯合时光谱特性的明显变化。在 20% 的二甲基亚砜（DMSO）稀释水溶液（1 × 10-6M）中，螯合和非金属螯合的 PRO-MOMIAs 的荧光强度基本相同。在金属离子大量过剩的情况下（铟的摩尔比为 1，铜的摩尔比为原 MOMIA 的 20 倍），原 MOMIA 的荧光强度会显著降低。这项研究表明，利用 MOMIAs 进行光学和放射性同位素联合成像是可行的。
• The hydroboration reaction as a key for a straightforward synthesis of new MRI-NCT agents
  作者：Paolo Boggio、Antonio Toppino、Simonetta Geninatti Crich、Diego Alberti、Domenica Marabello、Claudio Medana、Cristina Prandi、Paolo Venturello、Silvio Aime、Annamaria Deagostino

  DOI：10.1039/c4ob02291b

  日期：——

  A new lipophilic NCT/MRI agent has been synthesised in only four steps and characterised from the relaxometric point of view. This compound shows a high affinity for LDLs that can be loaded with 300 complexes per particle.

  一种新的亲脂性NCT/MRI试剂已经在仅四个步骤中合成，并从松弛度角度进行了表征。这种化合物显示出高亲和力LDL，每个粒子可以装载300个复合物。