[2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-(n-propyl)acetamide | 247085-49-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-(n-propyl)acetamide
• 英文别名: 2-(8-amino-2-(4-chlorophenyl) imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide；2-[8-amino-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide
• CAS: 247085-49-0
• 化学式: C₂₁H₂₅ClN₄O
• 分子量: 384.909
• InChiKey: CXVKFNSXWLQAPM-UHFFFAOYSA-N

物化性质

• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-(n-propyl)acetamide 在 吡啶 、 4-二甲氨基吡啶 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 7.0h， 生成 N1-(2-(4-chlorophenyl)-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-8-yl)-N6-(1-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)adipamide
  参考文献：
  名称：

  Translocator Protein (TSPO) Ligand−Ara-C (Cytarabine) Conjugates as a Strategy To Deliver Antineoplastic Drugs and To Enhance Drug Clinical Potential

  摘要：

  The aim of this work was to evaluate TSPO ligand-Ara-C conjugation as an approach for the selective delivery of the antineoplastic agent to brain tumors as well as for overcome P-gp resistance induction observed for the majority of cytotoxic agents, enhancing the drug clinical potential. To this end, the novel N-imidazopyridinacetyl-Ara-C conjugates 3a-c, 10 and 15 have been prepared and evaluated for their cytotoxicity against glioma cell lines. In contrast to that observed for 3a-c and 10, the conjugate 15 resulted stable in both phosphate buffer and physiological medium. In all cases, the release of free Ara-C from hydrolyzed conjugates was checked by HPLC and ESI-MS analysis. Conjugates 10 and 15 displayed very high in vitro TSPO affinity and selectivity, and, hence, they may possess potential for targeted brain delivery. Due to the favorable features displayed by the conjugate 15, it was further evaluated on glioma cell lines, expressing high levels of TSPO, in the presence and in the absence of specific nucleoside transport (NT) inhibitors. In contrast to that observed for the free Ara-C, the presence of NT inhibitors did not reduce the cytotoxic activity of 15. Moreover, conjugate 15, as N-4-acyl derivative of Ara-C, should be resistant to inactivation by cytidine deaminase, and it may possess enhanced propensity to target brain tumor cells characterized by a reduced expression of NTs. In addition, this conjugate behaves as a clear P-gp modulator and thereby may be useful to reverse MDR. Transport studies across the MDCKII-MDR1 monolayer indicated that conjugate 15 should overcome the BBB by transcellular pathway. All these features may be useful for enhancing the clinical potential of the nucleoside drug Ara-C.

  DOI：

  10.1021/mp100235w
• 作为产物：
  描述：

  2-氨基-3-硝基吡啶 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-(n-propyl)acetamide
  参考文献：
  名称：

  新型的2-苯基咪唑并[1,2-a]吡啶衍生物作为外围苯并二氮杂receptor受体的有效和选择性配体：合成，结合亲和力和体内研究。

  摘要：

  在两个中心位置（CBR）评估了一系列2-苯基咪唑并[1,2-a]吡啶乙酰胺在位置6和8（化合物17-31）以及酰胺氮（化合物32-40）上的取代基作用和外围（PBR）苯二氮卓受体。本文详细描述的结构-活性关系研究表明，高亲和力和选择性对PBR具有关键的结构特征。在位置8的咪唑并吡啶核上具有亲脂性取代基，并且在C（2）的苯环对位上存在一个氯原子，这对于高结合亲和力和对PBR的选择性至关重要。一小部分活性配体（即17，20，26，34，和35）在表达了克隆的人GABA（A）受体的非洲爪蟾卵母细胞中对CBR的作用进行了体外评估，并在体内评估了刺激类固醇如孕烯醇酮，孕酮，异戊四烯酮和异四氢脱氧皮质类固醇（THDOC）合成的能力。与化合物35不同，化合物17、20、26和34显着增加了血浆和大脑皮层中神经活性类固醇的水平。

  DOI：

  10.1021/jm991035g

文献信息

• 2-Phenyl-imidazo[1,2-<i>a</i>]pyridine Compounds Containing Hydrophilic Groups as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors: Synthesis, Binding Affinity and Electrophysiological Studies
  作者：Nunzio Denora、Valentino Laquintana、Maria Giuseppina Pisu、Riccardo Dore、Luca Murru、Andrea Latrofa、Giuseppe Trapani、Enrico Sanna

  DOI：10.1021/jm8006728

  日期：2008.11.13

  GABA A receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABA A receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion

  合成了一系列咪唑并吡啶乙酰胺，以评估中枢（CBR）和周围苯并二氮杂receptor受体（PBR）的结构变化的影响。这些变化包括在咪唑并吡啶骨架的2位和8位引入极性取代基或可电离的官能团。结果表明，在苯环的对位具有氢键受体和/或供体性质的取代基导致对PBR的高亲和力。在电生理研究中，发现化合物9、12、13和28显着增强了表达α1β2γ2 GABA A受体的非洲爪蟾卵母细胞中GABA诱发的Cl（-）电流。氟马西尼降低化合物9施加的刺激作用的能力支持以下结论：所检测化合物的调节作用涉及CBR。化合物16增加CA1锥体神经元中GABA A受体介导的微型抑制性突触后电流的能力表明其刺激神经甾体的局部合成和分泌的能力。
• New Fluorescent Probes Targeting the Mitochondrial-Located Translocator Protein 18 kDa (TSPO) as Activated Microglia Imaging Agents
  作者：Nunzio Denora、Valentino Laquintana、Adriana Trapani、Hiromi Suzuki、Makoto Sawada、Giuseppe Trapani

  DOI：10.1007/s11095-011-0552-0

  日期：2011.11

  PurposeTo evaluate the utility of new Translocator protein 18 kDa (TSPO)-targeted fluorescent probes for in vivo molecular imaging of activated microglia. MethodsCompounds 2–4 were synthesized; their stability and affinity for TSPO were determined. Compounds 2–4 were incubated both with Ra2 cells in the presence of LPS, a potent activator of microglia, and with tissue sections of normal and chemically

  目的评估新的 Translocator 蛋白 18 kDa (TSPO) 靶向荧光探针在活化小胶质细胞的体内分子成像中的效用。 方法合成了化合物2-4；测定了它们对 TSPO 的稳定性和亲和力。在 LPS（一种有效的小胶质细胞激活剂）存在下，将化合物 2-4 与 Ra2 细胞以及正常和化学损伤大脑的组织切片一起孵育。将化合物2-4注射入颈动脉或直接注射到小鼠的纹状体中。在组织化学处理后，通过荧光显微镜观察来自这些体外和体内研究的细胞和组织切片。 结果化合物 2-4 在缓冲液和生理介质中都很稳定，对 TSPO 显示出高亲和力，并被发现可以有效地染色活的 Ra2 小胶质细胞。Mito Tracker Red 双重染色表明，化合物 2 和 3 的结合位点可能存在于线粒体上。体内研究表明，化合物 2-4 可能部分渗入大脑；此外，小鼠纹状体中的细胞被化合物 2-4 和小胶质细胞标记物 CD11b 染色。
• Synthesis, Characterization, and Binding to the Translocator Protein (18 kDa, TSPO) of a New Rhenium Complex as a Model of Radiopharmaceutical Agents
  作者：Sara Piccinonna、Nunzio Denora、Nicola Margiotta、Valentino Laquintana、Giuseppe Trapani、Giovanni Natile

  DOI：10.1002/zaac.201300110

  日期：2013.7

  A new tridentate 2-phenyl-imidazopyridin-dipropylacetamide ligand (CB239-H) with high (nanomolar) affinity for the TSPO protein was synthesized and its coordination compound with rhenium tricarbonyl, fac-[Re(CO)3(CB239-N,N,O)] was investigated. The procedure established for the synthesis of the 187/185Re complex can be also used for the synthesis of 99mTc and 188/186Re analogues, which find application

  合成了一种对 TSPO 蛋白具有高（纳摩尔）亲和力的新型三齿 2-苯基-咪唑并吡啶-二丙基乙酰胺配体 (CB239-H) 及其与三羰基铼的配位化合物 fac-[Re(CO)3(CB239-N,N) ,O)] 进行了调查。为合成 187/185Re 复合物建立的程序也可用于合成 99mTc 和 188/186Re 类似物，这些类似物可用于 SPECT 诊断和治疗。由于 CB239-H 的三齿配位和羰基配体的动力学惰性，预计新复合物对血浆蛋白的反应性较低，因此对失活的抵抗力更强。TSPO 在多种类型的癌症和炎症性神经退行性疾病中发生的活化小胶质细胞中过度表达，TSPO 配体可用作受体介导的药物靶向载体，因此可用于诊断和治疗。非常令人惊讶的是，fac-[Re(CO)3(CB239-N,N,O)] 在稀释的人血清中不是很稳定，但对 TSPO 保持良好的亲和力。
• Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand
  作者：Nunzio Denora、Nicola Margiotta、Valentino Laquintana、Angela Lopedota、Annalisa Cutrignelli、Maurizio Losacco、Massimo Franco、Giovanni Natile

  DOI：10.1021/ml5000788

  日期：2014.6.12

  The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-selective ligand, 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)-acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)- N,N-dipropylacetamide (CB256), which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker.
• Platinum(II) Complexes with Bioactive Carrier Ligands Having High Affinity for the Translocator Protein
  作者：Nicola Margiotta、Nunzio Denora、Rosa Ostuni、Valentino Laquintana、Amy Anderson、Steven W. Johnson、Giuseppe Trapani、Giovanni Natile

  DOI：10.1021/jm100429r

  日期：2010.7.22

  Peripheral benzodiazepine receptors (PBRs, also named TSPO) are overexpressed in many tumor types, with the grade of TSPO overexpression correlating with the malignancy of the tumor. For this reason, TSPO-binding ligands have been widely explored as carriers for receptor-mediated drug delivery. In this paper we have selected a ligand with nanomolar affinity for TSPO, [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]]-N,N-di-n-propylacetamide (3), for preparing platinum adducts that are structural analogues to picoplatin, cis-[PtCl2(NH3)(2-picoline)] (AMD0473, 6), a platinum analogue currently in advanced clinical investigation. In vitro studies assessing receptor binding and cytotoxicity against human and rat glioma cells have shown that the new compounds cis-[PtX2(NH3)[2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-n-propylacetamidel}] (X = I,4; X = Cl, 5) keep high affinity and selectivity for TSPO (nanomolar concentration) and are as cytotoxic as cisplatin. Moreover, they appear to be equally active against sensitive and cisplatin-resistant A2780 cells. Similar to cisplatin, these compounds induce apoptosis but show a favorable 10- to 100-fold enhanced accumulation in the glioma cells.