3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid | 180152-83-4

• 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: 3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid
• 英文别名: 3,6,9-tris(2-(tert-butoxy)-2-oxo ethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecanoic acid；DTPA-tetra(tBu)ester；2-[2-[2-[bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]acetic acid
• CAS: 180152-83-4
• 化学式: C₃₀H₅₅N₃O₁₀
• 分子量: 617.781
• InChiKey: UCYDHTFZLUTQLJ-UHFFFAOYSA-N

物化性质

• 沸点：
  644.4±55.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  43
• 可旋转键数：
  24
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  152
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid 在 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 乙腈 为溶剂， 反应 6.5h， 生成 Tert-butyl 2-[2-[bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl-[2-[[2-[2-(2,5-dioxopyrrol-1-yl)ethylamino]-2-oxoethyl]-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate
  参考文献：
  名称：

  Reassessment of Diethylenetriaminepentaacetic Acid (DTPA) as a Chelating Agent for Indium-111 Labeling of Polypeptides Using a Newly Synthesized Monoreactive DTPA Derivative

  摘要：

  Previous studies on indium-111 (In-111) labeling of polypeptides and peptides using cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) as a bifunctional chelating agent (BCA) have indicated that DTPA might be a useful BCA for In-111 labeling of polypeptides at high specific activities when DTPA can be incorporated without inducing intra- or intermolecular cross-linking. To investigate this hypothesis, a monoreactive DTPA derivative with a maleimide group as the peptide binding site (MDTPA) was designed and synthesized. A monoclonal antibody (OST7, IgG(1)) was used as a model polypeptide, and conjugation of MDTPA with OST7, In-111 radiolabeling of MDTPA-OST7, and the stability of In-111-MDTPA-OST7 were investigated using cDTPA and benzyl-EDTA derivatives as references. SDS-PAGE analysis demonstrated that while cDTPA induced intramolecular cross-linking, no such undesirable side reactions were observed with MDTPA. MDTPA generated In-111-labeled OST7 with high radiochemical yields at higher specific activities than those produced using cDTPA and benzyl-EDTA derivatives as the BCAs. incubation of each In-111-labeled OST7 in human serum indicated that MDTPA generated In-111-labeled OST7 of much higher and a little lower stability than those derived from cDTPA and benzyl-EDTA derivatives, respectively. These findings indicated that the low in vivo stability of cDTPA-conjugated antibody reported previously is not attributable to low stability of In-111-DTPA but to formation of intramolecular cross-linking during cDTPA conjugation reactions. The present study also indicated that MDTPA and its precursor, the tetra-tert-butyl derivative of DTPA, would be useful BCAs for In-111 radiolabeling of polypeptides that have rapid blood clearance with high specific activities.

  DOI：

  10.1021/jm950949+
• 作为产物：
  描述：

  3-Benzyloxycarbonylmethyl-6,9-bis(t-butoxycarbonylmethyl)-3,6,9-triazaundecanedicarboxylic acid-di-t-butyl ester 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 6.0h， 以98%的产率得到3,6,9-tris(2-(tert-butoxy)-2-oxoethyl)-13,13-dimethyl-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid
  参考文献：
  名称：

  Reassessment of Diethylenetriaminepentaacetic Acid (DTPA) as a Chelating Agent for Indium-111 Labeling of Polypeptides Using a Newly Synthesized Monoreactive DTPA Derivative

  摘要：

  Previous studies on indium-111 (In-111) labeling of polypeptides and peptides using cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) as a bifunctional chelating agent (BCA) have indicated that DTPA might be a useful BCA for In-111 labeling of polypeptides at high specific activities when DTPA can be incorporated without inducing intra- or intermolecular cross-linking. To investigate this hypothesis, a monoreactive DTPA derivative with a maleimide group as the peptide binding site (MDTPA) was designed and synthesized. A monoclonal antibody (OST7, IgG(1)) was used as a model polypeptide, and conjugation of MDTPA with OST7, In-111 radiolabeling of MDTPA-OST7, and the stability of In-111-MDTPA-OST7 were investigated using cDTPA and benzyl-EDTA derivatives as references. SDS-PAGE analysis demonstrated that while cDTPA induced intramolecular cross-linking, no such undesirable side reactions were observed with MDTPA. MDTPA generated In-111-labeled OST7 with high radiochemical yields at higher specific activities than those produced using cDTPA and benzyl-EDTA derivatives as the BCAs. incubation of each In-111-labeled OST7 in human serum indicated that MDTPA generated In-111-labeled OST7 of much higher and a little lower stability than those derived from cDTPA and benzyl-EDTA derivatives, respectively. These findings indicated that the low in vivo stability of cDTPA-conjugated antibody reported previously is not attributable to low stability of In-111-DTPA but to formation of intramolecular cross-linking during cDTPA conjugation reactions. The present study also indicated that MDTPA and its precursor, the tetra-tert-butyl derivative of DTPA, would be useful BCAs for In-111 radiolabeling of polypeptides that have rapid blood clearance with high specific activities.

  DOI：

  10.1021/jm950949+

文献信息

• [EN] TUMOUR-TARGETING PEPTIDE VARIANTS<br/>[FR] VARIANTS PEPTIDIQUES CIBLANT DES TUMEURS
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018197490A1

  公开（公告）日：2018-11-01

  The present invention provides a peptide that selectively binds ανβ6 integrin, the peptide having an amino acid sequence comprising the motif X1BnRGDLX2X3X4 ZmX5, wherein X1 is any D-amino acid, Bn is a sequence of any n amino acids, which may be natural or unnatural, D- or L-, and may be the same or different, wherein n is a number between 1 and 10, X2 and X3 are independently selected from any amino acid, X4 is Leu or Ile, Zm is a sequence of any m amino acids, which may be natural or unnatural, D- or L-, and may be the same or different, wherein m is a number between 1 and 10, X5 is any L- or D-amino acid. Also provided are conjugates comprising said peptide, pharmaceutical compositions comprising said peptide or said conjugates, and uses of said peptide, conjugate or composition, for example, in the treatment, imaging and/or diagnosis of an ανβ6- expressing tumour in a mammalian subject.

  本发明提供了一种选择性结合ανβ6整合素的肽，该肽具有氨基酸序列，包括基序X1BnRGDLX2X3X4 ZmX5，其中X1是任何D-氨基酸，Bn是任何n个氨基酸的序列，可以是天然的或非天然的，D-或L-，可以相同也可以不同，其中n是1到10之间的数字，X2和X3分别选自任何氨基酸，X4是Leu或Ile，Zm是任何m个氨基酸的序列，可以是天然的或非天然的，D-或L-，可以相同也可以不同，其中m是1到10之间的数字，X5是任何L-或D-氨基酸。还提供了包括所述肽的结合物，包括所述肽或所述结合物的药物组合物，以及所述肽，结合物或组合物的用途，例如，在治疗、成像和/或诊断哺乳动物主体中表达ανβ6的肿瘤。
• Method for manufacturing diethylene triamine pentaacetic acid derivative
  申请人：Lee Te-Wei

  公开号：US20060264669A1

  公开（公告）日：2006-11-23

  The present invention at first prepares a penta-alkyl DTPA and then processes a regioselective hydrolysis over the penta-alkyl DTPA while using a metal ion as a catalyst to obtain a tetra-alkyl DTPA, where, by the above two steps, a monoreactive DTPA derivative is manufactured.

  该发明首先制备五烷基DTPA，然后在使用金属离子作为催化剂的情况下对五烷基DTPA进行区域选择性水解处理，从而获得四烷基DTPA，通过上述两个步骤，制造出一种单反应性DTPA衍生物。
• Methods and Compositions for Improved F-18 Labeling of Proteins, Peptides and Other Molecules
  申请人：McBride William J.

  公开号：US20080170989A1

  公开（公告）日：2008-07-17

  The present application discloses compositions and methods of synthesis and use of F-18 labeled molecules of use, for example, in PET imaging techniques. In particular embodiments, the labeled molecules may be peptides or proteins, although other types of molecules including but not limited to aptamers, oligonucleotides and nucleic acids may be labeled and utilized for such imaging studies. In preferred embodiments, the F-18 label may be conjugated to a targeting molecule by formation of a metal complex and binding of the F-18-metal complex to a chelating moiety, such as DOTA, NOTA, DTPA, TETA or NETA. In other embodiments, the metal may first be conjugated to the chelating group and subsequently the F-18 bound to the metal. In other preferred embodiments, the F-18 labeled moiety may comprise a targetable conjugate that may be used in combination with a bispecific or multispecific antibody to target the F-18 to an antigen expressed on a cell or tissue associated with a disease, medical condition, or pathogen. Exemplary results show that F-18 labeled targetable conjugate peptides are stable in human serum at 37° C. for several hours, sufficient time to perform PET imaging analysis.

  本申请公开了合成和使用F-18标记分子的组成物和方法，例如在PET成像技术中使用。在特定实施例中，标记的分子可以是肽或蛋白质，尽管其他类型的分子，包括但不限于apTAmer、寡核苷酸和核酸也可以被标记并用于这种成像研究。在优选实施例中，F-18标记可以通过形成金属配合物并将F-18金属配合物结合到螯合基团，例如DOTA、NOTA、DTPA、TETA或NETA，与靶向分子结合。在其他实施例中，金属可以首先与螯合基团结合，然后F-18与金属结合。在其他优选实施例中，F-18标记的分子可以包括可靶向的共轭物，可以与双特异性或多特异性抗体结合使用，以将F-18靶向表达在与疾病、医疗条件或病原体相关的细胞或组织上的抗原。示例结果表明，F-18标记的可靶向共轭肽在37℃的人血清中稳定数小时，足以进行PET成像分析。
• The influence of different metal-chelate conjugates of pentixafor on the CXCR4 affinity
  作者：Andreas Poschenrieder、Margret Schottelius、Markus Schwaiger、Horst Kessler、Hans-Jürgen Wester

  DOI：10.1186/s13550-016-0193-8

  日期：2016.12

  METHODS Cyclic pentapeptides, based on the pentixafor scaffold, were synthesized by a combined solid- and solution-phase peptide synthesis. The CXCR4 receptor affinities of the cold reference compounds were determined in competitive binding assays using CXCR4-expressing Jurkat T - cell leukemia cells and [(125)I]FC131 as the radioligand. RESULTS Metalated pentixafor derivatives with cyclic and acyclic

  背景技术趋化因子受体4（CXCR4）在不同的上皮，间充质和造血癌症中的过表达使CXCR4成为有吸引力的诊断和治疗靶标。但是，用小的基于五环五环的放射性药物靶向CXCR4受体仍然具有挑战性，因为配体-接头-螯合物结构内的微小结构修饰通常会显着影响受体亲和力。基于CXCR4指导的五肽[（68）Ga] pentixafor（环（-D-Tyr-N-Me-D-Orn（AMB-DOTA）-L-Arg-L-2-Nal- （Gly-）），这项研究旨在拓宽适用的（放射性）金属标记的pentixa用于类似物的范围。方法通过固相和溶液相肽合成方法合成了基于pentixafor支架的环状五肽。使用表达CXCR4的Jurkat T细胞白血病细胞和[（125）I] FC131作为放射性配体，在竞争结合试验中确定了冷参考化合物的CXCR4受体亲和力。结果通过固相肽合成法合成了具有环状和非环状螯合剂的金属化戊酯衍生物，并
• Synthesis of DTPA-conjugated (1,4)-linked 2-aminoglycosides varying in the anomeric configuration and their MRI contrast effect
  作者：Hiroshi Tanaka、Yoshio Ando、Masatoshi Wada、Takashi Takahashi

  DOI：10.1039/b507824e

  日期：——

  We describe the efficient synthesis of DTPA-conjugated oligosaccharides composed of α- and/or β-linked tri to monoglucosamines. Gd(III) complex with DTPA-conjugated chitotriitol 1 has been reported to be an effective MRI contrast agent. In order to elucidate the structure–property relationships, we planned to synthesize the DTPA-conjugated 2-amino-tri-, di-, and monosaccharides varying in configuration at the anomeric positions and the C2 position on the reducing end. Our strategy for the synthesis of the DTPA-conjugated oligosaccharides involves O-perbenzyl protected 2-amino-tri-, di-, and monosaccharides as key intermediates. The 2-aminoglycosides were prepared by non-selective glycosidation of 2-azido-2-deoxyglycosyl donors, followed by separation of two anomeric isomers. Although the synthesis involves separation of the stereoisomers, it circumvents not only the careful tuning of reaction conditions, but also the time-consuming preparation of glycosyl donors attached to different protecting groups. The protected 2-aminoglycosides were converted to the fully deprotected DTPA-conjugated tri- to monosaccharides by the same operation. MRI phantom study using the Gd(III) complexes of DTPA-conjugated oligosaccharides indicates that the number of the monosaccharide units was critical for enhancing the relative signal intensity of water protons per Gd, and various stereoisomers would be candidate scaffolds for MRI contrast agents.

  我们描述了由α-和/或β-连接的三葡糖胺与单葡糖胺组成的 DTPA 共轭寡糖的高效合成。据报道，Gd（III）与 DTPA 共轭壳三醇 1 的复合物是一种有效的磁共振成像造影剂。为了阐明其结构-性质关系，我们计划合成 DTPA 键合的 2-氨基三糖、二糖和单糖，它们在异构体位置和还原端 C2 位置的构型各不相同。我们合成 DTPA 共轭寡糖的策略是以 O-perbenzyl 保护的 2-氨基三糖、二糖和单糖为关键中间体。2-aminoglycosides 是通过 2-azido-2-deoxyglycosyl 给体的非选择性糖苷化反应制备的，然后分离出两种异构体。虽然这种合成方法涉及立体异构体的分离，但它不仅避免了对反应条件的精心调整，还避免了制备连接不同保护基团的糖基供体的耗时过程。通过同样的操作，受保护的 2-氨基糖苷被转化为完全去保护的 DTPA 共轭三糖和单糖。使用 DTPA 共轭低聚糖的 Gd(III) 复合物进行的磁共振成像模型研究表明，单糖单元的数量对于增强每个 Gd 的水质子的相对信号强度至关重要，各种立体异构体将成为磁共振成像造影剂的候选支架。