8-(4-羧甲基氧基)苯基-1,3-二丙基黄嘌呤 | 96865-83-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 8-(4-羧甲基氧基)苯基-1,3-二丙基黄嘌呤
• 英文名称: XCC
• 英文别名: 8-<4-<(carboxymethyl)oxy>phenyl>-1,3-dipropylxanthine；8-{4-[(carboxymethyl)oxy]phenyl}-1,3-dipropylxanthine；[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy]acetic acid；2-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)phenoxy]acetic acid
• CAS: 96865-83-7
• 化学式: C₁₉H₂₂N₄O₅
• 分子量: 386.407
• InChiKey: QTMMGCYGCFXBFI-UHFFFAOYSA-N

物化性质

• 溶解度：
  在DMSO中溶解至50mM

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 储存条件：
  -20°C，干燥

反应信息

• 作为反应物：
  描述：

  8-(4-羧甲基氧基)苯基-1,3-二丙基黄嘌呤 在 吡啶 、 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 28.0h， 生成 8-[4-[((4-Methoxycarbonyl)phenylcarbamoylmethyl)oxy]phenyl]-1,3-di-(n-propyl)xanthine
  参考文献：
  名称：

  8-苯基黄嘌呤羧酸同系物的苯胺衍生物是人类 A(2B) 腺苷受体的高效和选择性拮抗剂。

  摘要：

  没有报道 A(2B) 腺苷受体 (AR) 的高选择性拮抗剂；然而，这样的拮抗剂具有作为平喘剂的治疗潜力。在这里，我们报告了有效和选择性 A(2B) 受体拮抗剂的合成。8-苯基-1, 3-二-(n-丙基)黄嘌呤衍生物与 HEK-293 细胞 (HEK-A(2B)) 中重组人 A(2B) ARs 结合的构效关系 (SAR) 和探索了其他 AR 亚型。合成了 8-[4-[[羧甲基]氧基]苯基]-1,3-二-(正丙基)黄嘌呤 4a 的各种酰胺衍生物。芳基、烷基和芳烷基酰胺的比较表明，简单的苯胺，特别是在对位被吸电子基团取代的那些，例如硝基、氰基和乙酰基，可选择性地结合范围内的人 A(2B) 受体1-3 nM。未取代的苯胺 12 在 A(2B) 受体处的 K(i) 值为 1.48 nM，但对人类 A(1)/A(2A) 受体和非选择性对大鼠 A(1) 受体仅具有中等选择性。高效和选择性 A(2B) 拮抗剂是对氨基苯乙酮衍生物

  DOI：

  10.1021/jm990421v
• 作为产物：
  描述：

  8-(4'-Carboxymethyloxyphenyl)-1,3-dipropylxanthine ethyl ester 在 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 8-(4-羧甲基氧基)苯基-1,3-二丙基黄嘌呤
  参考文献：
  名称：

  1,3-二烷基黄嘌呤的功能化同系物：制备对腺苷受体具有高亲和力的类似物。

  摘要：

  一系列功能化的 1,3-二烷基黄嘌呤同源物已被制备作为腺苷受体拮抗剂。基于8-(对羟基苯基)-1,3-二烷基黄嘌呤的高效力，母体化合物是茶碱和1,3-二丙基黄嘌呤的8-[4-[(羧甲基)氧基]苯基]衍生物。制备了一系列类似物，包括乙醇和N-羟基琥珀酰亚胺的酯、酰胺、酰肼、酰基脲和苯胺。阻断 A1-腺苷受体（抑制 N6-[3H]环己基腺苷与脑膜的结合）和 A2-腺苷受体（抑制 2-氯腺苷引起的脑切片中环 AMP 积累）的效力受到结构变化的显着影响位于主要药效基团（8-苯基-1,3-二烷基黄嘌呤）的远端。二丙基系列对 A1 受体的效力范围从具有末端酰胺基乙烯胺部分的同源物的 Ki 值 1.2 nM，到母体羧酸的 Ki 值 58 nM，再到庞大的脲基同源物的 Ki 值 96 nM。某些同系物对 A1 受体的活性比对 A2 受体的活性高 145 倍。同系物的各种衍生物应可用作受体探针并用于放射性碘标记、抗生物素蛋白结合和亲和柱的制备。

  DOI：

  10.1021/jm00147a038

文献信息

• Biologically-active 1,3-dipropyl-8-phenylxanthine derivatives
  申请人：The United States of America as represented by the Department of Health

  公开号：US04612315A1

  公开（公告）日：1986-09-16

  Certain functionalized congeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A.sub.1 - and A.sub.2 -adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl at the 8 position para-substituted with a functionalized chain to provide high water solubility and high receptor affinity to such an extent that these compounds are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.

  某些功能化的1,3-二烷基黄嘌呤衍生物作为A.sub.1-和A.sub.2-腺苷受体的拮抗剂表现出高效性和选择性，并适合连接到探针、药物载体或固体支持物上。这些衍生物的特点是在8位置带有苯基，对位取代为功能化链以提供高水溶性和高受体亲和力，使得这些化合物适合用作抗过敏、抗哮喘或强心药、中枢神经系统兴奋剂和利尿剂。
• Biologically-active xanthine derivatives
  申请人：The United States of America as represented by the Department of Health

  公开号：US04696932A1

  公开（公告）日：1987-09-29

  Certain functionalized cogeners of 1,3-dialkylxanthine exhibit high potency and selectivity as antagonists for A.sub.1 - and A.sub.2 -adenosine receptors and are suitable for attachment to probes, drug carriers, or solid supports. These derivatives are characterized by the presence of a phenyl at the 8 position para-substituted with a functionalized chain to provide high water solubility and high receptor affinity. Some of these analogs, containing a distal amino- or carboxylic-functionalized chain, are suitable for synthesis of amino acid conjugates. The compounds of this invention are suitable for use as antiallergenic, antiasthmatic, or cardiotonic drugs, central nervous system stimulants, and diuretics.

  1,3-二烷基黄嘌呤的某些官能化同系物表现出高效和选择性，作为A.sub.1-和A.sub.2-腺苷受体的拮抗剂，并适合附着到探针、药物载体或固体支撑物上。这些衍生物的特点是在8位存在一个苯基，对位取代一个官能化链以提供高水溶性和高受体亲和力。其中一些含有远端氨基或羧基官能化链的类似物，适合用于合成氨基酸共轭物。本发明的化合物适用于用作抗过敏、抗哮喘或心脏强心药、中枢神经系统兴奋剂和利尿剂。
• Kinetic profiling and functional characterization of 8-phenylxanthine derivatives as A2B adenosine receptor antagonists
  作者：Anna Vlachodimou、Henk de Vries、Milena Pasoli、Miranda Goudswaard、Soon-Ai Kim、Yong-Chul Kim、Mirko Scortichini、Melissa Marshall、Joel Linden、Laura H. Heitman、Kenneth A. Jacobson、Adriaan P. IJzerman

  DOI：10.1016/j.bcp.2022.115027

  日期：2022.6

  the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as A2BAR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All

  A 2B腺苷受体 (A 2B AR) 拮抗剂在炎症相关疾病如哮喘、慢性阻塞性肺病和癌症中具有治疗潜力。然而，目前还没有药物获得临床批准，从而产生了对新型拮抗剂研究的需求。在过去的十年中，靶点结合动力学以及亲和力和效力的研究已被证明在早期药物发现阶段很有价值，因为它与体内药物疗效和安全性的提高有关。在这项研究中，我们将一系列黄嘌呤衍生物的合成和生物学评价报告为 A 2BAR拮抗剂，包括设计用于与受体共价结合的异硫氰酸酯衍生物。在放射性配体结合实验中评估了所有 28 种最终化合物，以评估它们的亲和力和那些合格的动力学结合参数。推导了结构-亲和力和结构-动力学关系，提供了亲和力和解离速率常数之间的明确关系。两种结构相似的化合物17和18由于其不同的动力学特征，在无标记测定中进一步评估。延长的细胞反应与较长的 A 2B AR 停留时间有关。配体的 A 2B之间的这种联系AR 停留时间及其功能效应突
• Adenosine A_2A Receptor-Antagonist/Dopamine D₂ Receptor-Agonist Bivalent Ligands as Pharmacological Tools to Detect A_2A-D₂ Receptor Heteromers
  作者：Aroa Soriano、Ruben Ventura、Anabel Molero、Rob Hoen、Vicent Casadó、Antoni Cortés、Francesca Fanelli、Fernando Albericio、Carmen Lluís、Rafael Franco、Miriam Royo

  DOI：10.1021/jm900298c

  日期：2009.9.24

  Adenosine A(2A) (A(2A)R) and dopamine D-2 (D2R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D,R agonist and an A2AR antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D2R heteromers. Bivalent ligands with shorter linkers bound to D2R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D2R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D2R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
• Electrophilic derivatives of purines as irreversible inhibitors of A1 adenosine receptors
  作者：Kenneth A. Jacobson、Suzanne Barone、Udai Kammula、Gary L. Stiles

  DOI：10.1021/jm00125a019

  日期：1989.5

  Functionalized congeners derived from 1,3-dipropyl-8-phenylxanthine and from N6-phenyladenosine were derivatized to contain electrophilic groups (isothiocyanate, N-hydroxysuccinimide ester, maleimide, sulfonyl chloride, or alpha-haloacyl group) capable of reaction with nucleophiles on biopolymers. The goal was to inhibit chemically the A1 adenosine receptor by using reactive agonist and antagonist ligands. Some of the electrophilic derivatives were synthesized through acylation of amine-functionalized congeners using hetero- or homobifunctional reagents available for protein cross-linking. The affinity for A1 adenosine receptors was evaluated in competitive binding assays by using rat and bovine brain membranes. Several xanthine and adenosine thiourea derivatives prepared from 1,3- and 1,4-phenylene diisothiocyanate (DITC) were potent irreversible inhibitors of adenosine receptors. Derivatives of m-DITC, at concentrations between 10 and 500 nM, irreversibly eliminated binding at 90% of the A1-receptor sites. Receptor affinity of both xanthine and adenosine derivatives containing distal phenylthiourea substituents was diminished by electron-donating groups on the ring.