N²-N,N-dimethylaminomethylene-10-formylpteoric acid | 1046806-28-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N²-N,N-dimethylaminomethylene-10-formylpteoric acid
• 英文别名: N²,N,N-dimethylaminomethylene-10-formyl-pteroic acid；4-[[2-(dimethylaminomethylideneamino)-4-oxo-3H-pteridin-6-yl]methyl-formylamino]benzoic acid
• CAS: 1046806-28-3
• 化学式: C₁₈H₁₇N₇O₄
• 分子量: 395.377
• InChiKey: HLZGNBPKNFDZBI-UHFFFAOYSA-N

物化性质

• 沸点：
  642.2±65.0 °C(Predicted)
• 密度：
  1.46±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  140
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N²-N,N-dimethylaminomethylene-10-formylpteoric acid 在 copper diacetate sodium hydroxide 、 水 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 sodium ascorbate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 2.33h， 生成
  参考文献：
  名称：

  WO2008/125618

  摘要：

  公开号：
• 作为产物：
  描述：

  N,N-二甲基甲酰胺二异丙基缩醛 、 4-[(2-氨基-4-氧代-1H-蝶啶-6-基)甲基-甲酰氨基]苯甲酸 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 N²-N,N-dimethylaminomethylene-10-formylpteoric acid
  参考文献：
  名称：

  WO2008/125618

  摘要：

  公开号：

文献信息

• [EN] 18F-SACCHARIDE-FOLATES<br/>[FR] 18F-SACCHARIDE-FOLATES
  申请人：MERCK & CIE

  公开号：WO2013026842A1

  公开（公告）日：2013-02-28

  The present invention is directed towards new 18F-folate radiopharmaceuticals, wherein the 18Fisotope is linked via a prosthetic group, more specifically via a prosthetic group having a saccharide group, such as acyclic mono-or oligosaccharide, preferably based on a pyranoside or furanoside, which is covalently linked to the glutamate portion of a folateor derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.

  本发明涉及新的18F-叶酸放射性药物，其中18F同位素通过一个假体基团连接，更具体地通过一个具有糖苷基团的假体基团连接，例如非环式单糖或寡糖，最好基于吡喃糖苷或呋喃糖苷，它与叶酸或其衍生物的谷氨酸部分共价连接，以及它们的制备方法，以及它们在癌症、炎症和自身免疫疾病的诊断和监测以及治疗中的应用。
• 18F-SACCHARIDE-FOLATES
  申请人：Schibli Roger

  公开号：US20140193337A1

  公开（公告）日：2014-07-10

  The present invention is directed towards new 18 F-folate radiopharmaceuticals, wherein the 18 F isotope is linked via a prosthetic group, more specifically via a prosthetic group having a saccharide group, such as a cyclic mono- or oligosaccharide, preferably based on a pyranoside or furanoside, which is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.

  本发明涉及新的18F-叶酸类放射性药物，其中18F同位素通过一个假体基团连接，更具体地说是通过一个带有糖苷基团的假体基团连接，比如基于吡喃苷或呋喃苷的环状单糖或寡糖，该基团共价连接到叶酸或其衍生物的谷氨酸部分，以及它们的制备方法，以及在癌症、炎症性和自身免疫性疾病的诊断和监测以及治疗中的使用。
• Organometallic 99mTc-technetium(I)- and Re-rhenium(I)-folate derivatives for potential use in nuclear medicine
  作者：Cristina Müller、Cécile Dumas、Ute Hoffmann、P. August Schubiger、Roger Schibli

  DOI：10.1016/j.jorganchem.2004.08.045

  日期：2004.12

  α-folate derivative or – if directly attached to pteroic acid – the pteroate derivative. The derivatives were reacted with the precursor [M(OH2)3(CO)3]+ (M = 99mTc, Re) to form uniform organometallic folate complexes under mild reaction conditions. All compounds were chemically characterized by means of NMR, MS, IR and HPLC. The determination of the IC50-values for the PAMA-γ-folate derivative (100 nM)

  叶酸受体（FR）是一种高亲和力的膜蛋白，在多种肿瘤细胞中过表达，但在正常组织中高度受限。因此标记有短的生活叶酸衍生物的同位素如99米TC（γ，吨1/2  = 6小时）或188的Re（β - ，吨1/2 = 17 h）可用于肿瘤的诊断和治疗。在这方面，开发有机金属tech（I）和rh（I）改性的叶酸放射性药物引起了极大的兴趣。为此，将叶酸用三齿苦味酚胺单乙酸螯合系统官能化。螯合系统通过氨基己烷间隔基选择性地偶联到叶酸谷氨酸部分的γ-或α-羧基上，以获得相应的γ-或α-叶酸衍生物，或者-如果直接与蝶酸相连-则是蝶酸衍生物。衍生物与前体[M（OH 2）3（CO）3 ] +（M =  99mTc，Re）在温和的反应条件下形成均匀的有机金属叶酸络合物。所有化合物均通过NMR，MS，IR和HPLC进行化学表征。对PAMA-γ-叶酸衍生物（100 nM）和相应的有机金属rh络合物（110 nM）的IC 50值的测定证明保留了受体结合特性。[
• Synthesis of a Novel γ-Folic Acid-<i>N</i> ^τ-Histidine Conjugate Suitable for Labeling with ^99mTc and ¹⁸⁸Re
  作者：Viola Groehn、Christof Sparr、Urs Michel、Roger Marti、Cristina Müller、Roger Schibli、Rudolf Moser

  DOI：10.1055/s-0028-1083345

  日期：——

  coupled to protected pteroic acid to give 1 in two steps in 47% yield. N τ-(Functionalized aminoalkyl)histidine was synthesized by two different routes. The preferred route starting from Boc-His-OMe led in two steps to the N τ-(functionalized amino­alkyl)histidine in 36% yield. alkylations - amino acids - regioselectivity - organometallic - receptor

  放射性标记的叶酸衍生物具有靶向叶酸受体阳性肿瘤细胞的潜能，可用于无创诊断和治疗。我们报告一个新的γ-叶酸酸的合成Ñ τ组氨酸偶联物1，其中Ñ τ组氨酸是适合于与同位素放射性标记99米TC（诊断）和¹88的Re（治疗）。一种模块化的合成策略应用于：Ñ α -Boc-α羧基-保护的谷氨酸被amidically链接到Ñ τ -经由γ-羧基（官能化氨基烷基）组氨酸，以形成结构单元8。中级8将其与受保护的蝶酸偶联，分两步得到1，收率47％。Ñ τ - （官能氨基烷基）组氨酸是由两个不同的途径合成。由Boc-的His-OME开始，优选的途径导致在两个步骤中对Ñ τ - （官能氨基烷基），收率36％组氨酸。 烷基化-氨基酸-区域选择性-有机金属-受体
• Comparative Studies of Three Pairs of α- and γ-Conjugated Folic Acid Derivatives Labeled with Fluorine-18
  作者：Silvan D. Boss、Thomas Betzel、Cristina Müller、Cindy R. Fischer、Stephanie Haller、Josefine Reber、Viola Groehn、Roger Schibli、Simon M. Ametamey

  DOI：10.1021/acs.bioconjchem.5b00644

  日期：2016.1.20

  The folate receptor (FR) is upregulated in various epithelial cancer types (FR α-isoform), while healthy tissues show only restricted expression. FR-targeted imaging using folate radiopharmaceuticals is therefore a promising approach for the detection of FR-positive cancer tissue. Almost all folate-based radiopharmaceuticals have been prepared by conjugation at the γ-carboxylic functionality of the glutamate moiety of folic acid. In this work, three pairs of fluorinated α- and γ-conjugated folate derivatives were synthesized and their in vitro and in vivo properties compared. The syntheses of all six regioisomers were obtained in good chemical yields using a multistep synthetic approach including the highly selective Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radiosyntheses of the α- and γ-conjugated 18F-labeled folate derivatives were accomplished in moderate to good radiochemical yields, high radiochemical purities (>95%), and specific activities ranging from 25 to 196 GBq/μmol. In vitro, all folate derivatives showed high binding affinity to the FR-α (IC50 = 1.4–2.2 nM). In vivo PET imaging and biodistribution studies in FR-positive KB tumor-bearing mice demonstrated similar FR-specific tumor uptake for both regioisomers of each pair of compounds. However, FR-unspecific liver uptake was significantly lower for the α-regioisomers compared to the corresponding γ-regioisomers. In contrast, kidney uptake was up to 50% lower for the γ-regioisomers than for the α-regioisomers. These results show that the site of conjugation in the glutamyl moiety of folic acid has a significant impact on the in vivo behavior of 18F-based radiofolates, but not on their in vitro FR-binding affinity. These findings may potentially stimulate new directions for the design of novel 18F-labeled folate-based radiotracers.

  叶酸受体（FR）在各种上皮癌（FR α-异构体）中上调，而在健康组织中只显示有限的表达。因此，使用叶酸放射性药物进行 FR 靶向成像是检测 FR 阳性癌症组织的一种很有前景的方法。几乎所有基于叶酸的放射性药物都是通过在叶酸谷氨酸分子的γ-羧基官能团上进行共轭制备的。在这项工作中，合成了三对氟化α-和γ-共轭叶酸衍生物，并比较了它们的体外和体内特性。采用多步合成方法，包括高选择性的 Cu（I）催化 1,3-二极环化反应，以良好的化学收率合成了所有六种区域异构体。α-和γ-共轭的 18F 标记叶酸衍生物的放射合成具有中等至良好的放射化学收率、较高的放射化学纯度（>95%）和 25 至 196 GBq/μmol 的比活度。在体外，所有叶酸衍生物都显示出与 FR-α 的高结合亲和力（IC50 = 1.4-2.2 nM）。在 FR 阳性 KB 肿瘤小鼠体内进行的 PET 成像和生物分布研究表明，每对化合物的两种区域异构体都有类似的 FR 特异性肿瘤摄取。然而，与相应的γ-区域异构体相比，α-区域异构体对FR-非特异性肝脏摄取量明显较低。相反，肾脏对γ-雷焦异构体的摄取量比对α-雷焦异构体的摄取量低 50%。这些结果表明，叶酸谷酰胺酰基中的共轭部位对 18F 放射性叶酸盐的体内行为有重大影响，但对其体外 FR 结合亲和力没有影响。这些发现有可能为设计新型 18F 标记叶酸类放射性示踪剂提供新的方向。