1-propyl-8-[4-[[[p-nitrophenyl]oxy]sulfonyl]phenyl]xanthine | 666716-07-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 1-propyl-8-[4-[[[p-nitrophenyl]oxy]sulfonyl]phenyl]xanthine
• 英文别名: 1-propyl-8-[4-[[p-nitrophenoxy]sulfonyl]phenyl]xanthine；4-(2,6-Dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-benzenesulfonic acid 4-nitro-phenyl ester；(4-nitrophenyl) 4-(2,6-dioxo-1-propyl-3,7-dihydropurin-8-yl)benzenesulfonate
• CAS: 666716-07-0
• 化学式: C₂₀H₁₇N₅O₇S
• 分子量: 471.45
• InChiKey: GRIXSFHJKXADFX-UHFFFAOYSA-N

物化性质

• 熔点：
  >300 °C
• 密度：
  1.507±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  176
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(1-苯基乙基)哌嗪 、 1-propyl-8-[4-[[[p-nitrophenyl]oxy]sulfonyl]phenyl]xanthine 以 二甲基亚砜 为溶剂， 反应 3.0h， 以41%的产率得到8-(4-((4-(1-phenylethyl)piperazin-1-yl)sulfonyl)phenyl)-1-propyl-3,7-dihydropurine-2,6-dione
  参考文献：
  名称：

  A_2B Adenosine Receptor Antagonists with Picomolar Potency

  摘要：

  The A(2B) adenosine receptor (A(2B)AR) was proposed as a novel target for the (immuno)therapy of cancer since A(2B)AR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A(2B)AR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A(2B)-antagonist (K-i 0.0835 nM, K-B 0.0598 nM, human A(2B)AR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A(2B)AR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.

  DOI：

  10.1021/acs.jmedchem.9b00071
• 作为产物：
  描述：

  potassium p-carboxybenzenesulfonate 在 氯磺酸 、 sodium hydroxide 、 polyphosphoric acid trimethylsilyl ester 、 Tris-HCl buffer 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 4.0h， 生成 1-propyl-8-[4-[[[p-nitrophenyl]oxy]sulfonyl]phenyl]xanthine
  参考文献：
  名称：

  磺基苯基黄嘌呤硝基苯酯的制备，性质，反应和腺苷受体亲和力：对具有经口生物利用度的磺酸前药的发展。

  摘要：

  P2嘌呤能受体的许多目前已知的拮抗剂是带有一个或几个苯基磺酸酯基的阴离子分子。在P1（腺苷）受体拮抗剂中，黄嘌呤苯磺酸盐是一类有效的化合物。由于它们的高酸度，苯磺酸盐在生理pH值下带负电荷，并且不易穿透细胞膜。本研究旨在通过将磺酸盐转化为化学稳定的硝基苯基酯来开发其亲脂性，口服可生物利用的前药。使用甲苯磺酸硝基苯酯作为模型化合物在不同pH值下进行的初始稳定性测试表明，间硝基苯酯在很宽的pH范围内都是稳定的，而邻位和对位异构体在强酸性或碱性条件下则较不稳定。合成了对磺基苯基黄嘌呤衍生物的一系列间硝基和对硝基苯基酯作为模型化合物。通过在碳二亚胺存在下将合适的5,6-二氨基尿嘧啶与4-（硝基苯氧基磺酰基）苯甲酸缩合，然后用多磷酸三甲基甲硅烷基酯闭环，以高收率获得目标黄嘌呤衍生物。通过毛细管电泳在体外研究了间硝基苯酯的化学和酶稳定性。观察到在水溶液，人造胃酸和血清中的高稳定性。但是，用作原型黄嘌呤

  DOI：

  10.1021/jm0310030

文献信息

• Preparation, Properties, Reactions, and Adenosine Receptor Affinities of Sulfophenylxanthine Nitrophenyl Esters:  Toward the Development of Sulfonic Acid Prodrugs with Peroral Bioavailability
  作者：Luo Yan、Christa E. Müller

  DOI：10.1021/jm0310030

  日期：2004.2.1

  esters of p-sulfophenylxanthine derivatives were synthesized as model compounds. The target xanthine derivatives were obtained in high yields by condensation of the appropriate 5,6-diaminouracils with 4-(nitrophenoxysulfonyl)benzoic acids in the presence of a carbodiimide, followed by ring closure with polyphosphoric acid trimethylsilyl ester. The chemical and enzymatic stability of the m-nitrophenyl

  P2嘌呤能受体的许多目前已知的拮抗剂是带有一个或几个苯基磺酸酯基的阴离子分子。在P1（腺苷）受体拮抗剂中，黄嘌呤苯磺酸盐是一类有效的化合物。由于它们的高酸度，苯磺酸盐在生理pH值下带负电荷，并且不易穿透细胞膜。本研究旨在通过将磺酸盐转化为化学稳定的硝基苯基酯来开发其亲脂性，口服可生物利用的前药。使用甲苯磺酸硝基苯酯作为模型化合物在不同pH值下进行的初始稳定性测试表明，间硝基苯酯在很宽的pH范围内都是稳定的，而邻位和对位异构体在强酸性或碱性条件下则较不稳定。合成了对磺基苯基黄嘌呤衍生物的一系列间硝基和对硝基苯基酯作为模型化合物。通过在碳二亚胺存在下将合适的5,6-二氨基尿嘧啶与4-（硝基苯氧基磺酰基）苯甲酸缩合，然后用多磷酸三甲基甲硅烷基酯闭环，以高收率获得目标黄嘌呤衍生物。通过毛细管电泳在体外研究了间硝基苯酯的化学和酶稳定性。观察到在水溶液，人造胃酸和血清中的高稳定性。但是，用作原型黄嘌呤
• A New Synthesis of Sulfonamides by Aminolysis of <i>p</i>-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A_2B Receptor Antagonists
  作者：Luo Yan、Daniela C. G. Bertarelli、Alaa M. Hayallah、Heiko Meyer、Karl-Norbert Klotz、Christa E. Müller

  DOI：10.1021/jm060277v

  日期：2006.7.1

  N-benzylpiperazine reacted with p-nitrophenoxysulfonylphenylxanthine derivatives yielding the desired sulfonamides in satisfying to very good yields. The obtained sulfonamides were much more potent at A(2B) receptors than the parent sulfonates. The most active compound of the present series was 8-[4-(4-benzylpiperazide-1-sulfonyl)phenyl]-1-propylxanthine (11, PSB-601) exhibiting a K(i) value of 3.6 nM

  1-丙基和1,3-二甲基-8-对磺基苯基黄嘌呤（PSB-1115和SPT）被用作开发具有磺酰胺结构的腺苷A（2B）受体拮抗剂的起始化合物。由于磺酰胺形成的标准反应失败或导致非常低的收率，我们开发了一种制备磺酰胺的新方法。对硝基苯酚用作具有良好平衡的稳定性-反应性的合适的离去基团。各种各样的胺，包括苯胺，苄胺，苯乙胺，丙胺，丁胺，2-羟乙胺，氨基乙酸和N-苄基哌嗪与对硝基苯氧基磺酰基苯基黄嘌呤衍生物反应，可产生所需的磺酰胺，以非常令人满意的产率获得。所获得的磺酰胺类对A（2B）受体的作用比其母体的磺酸盐强得多。
• Synthesis of Novel Fluorinated Xanthine Derivatives with High Adenosine A2B Receptor Binding Affinity
  作者：Marcel Lindemann、Sladjana Dukic-Stefanovic、Sonja Hinz、Winnie Deuther-Conrad、Rodrigo Teodoro、Cathleen Juhl、Jörg Steinbach、Peter Brust、Christa E. Müller、Barbara Wenzel

  DOI：10.3390/ph14050485

  日期：——

  protein-coupled adenosine A2B receptor is suggested to be involved in various pathological processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A2B receptor is currently in focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of

  G蛋白偶联的腺苷A 2B受体被认为与各种病理过程有关，伴随着在炎症，缺氧和癌症中发现的腺苷水平升高。因此，腺苷A 2B受体目前正成为癌症治疗以及通过正电子发射断层扫描（PET）进行的非侵入性分子成像的新型靶标。为了开发一种用PET放射性核素氟18标记的放射性示踪剂对脑肿瘤中的腺苷A 2B受体成像，最有效和选择性的拮抗剂之一，黄嘌呤衍生物PSB-603被选为先导化合物。最初的小鼠生物分布研究表明，[ 3 H] PSB-603（SUV3min：0.2），进行结构修饰以优化关于血脑屏障渗透的理化特性。合成了两个带有2-氟吡啶（5）部分和4-氟-哌啶（6）部分的新型氟化衍生物，并在竞争结合试验中确定了它们对4种腺苷受体亚型的亲和力。与其他腺苷受体亚型相比，这两种化合物均显示出对腺苷A 2B受体的高亲和力（K i（5）= 9.97±0.86 nM；K i（6）= 12.3±3.6 nM）。
• 1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: Development and Characterization of Adenosine A_2B Receptor Antagonists and a New Radioligand with Subnanomolar Affinity and Subtype Specificity
  作者：Thomas Borrmann、Sonja Hinz、Daniela C. G. Bertarelli、Wenjin Li、Nicole C. Florin、Anja B. Scheiff、Christa E. Müller

  DOI：10.1021/jm900413e

  日期：2009.7.9

  A new series of 1-alkyl-8-(piperazine-1-sulfonyl)phenylxanthines was designed, synthesized, and characterized in radioligand binding and functional assays at A(2B) adenosine receptors. A(2B) antagonists with subnanomolar affinity and high selectivity were discovered. The most potent compounds were 1-ethyl-8-(4-(4-(4-trifluoromethylbenzyl)piperazine-1-sulfonyl)phenyl)xanthine (24, PSB-09120, K-i (human A(2B)) = 0. 157 nM) and 8-(4-(4-(4-chlorobenzyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (17, PSB-0788, K-i (human A2(B)) = 0.393 nM). Moreover, 8-(4-(4-(4-chlorophenyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (35, PSB-603) was developed as an A(2B)-specific antagonist exhibiting a Ki value of 0.553 nM at the human A2B receptor and virtually no affinity for the human and rat A(1) and A(2A) and the human A(3) receptors up to a concentration of 10 mu M. A tritiated form of the compound was prepared as a new radioligand and characterized in kinetic, saturation, and competition studies. It was shown to be a useful pharmacological tool for the selective labeling of human as well as rodent A(2B) receptors (K-D human A(2B) 0.403 nM, mouse A(2B) 0.351 nM).
• A_2B Adenosine Receptor Antagonists with Picomolar Potency
  作者：Jie Jiang、Catharina Julia Seel、Ahmed Temirak、Vigneshwaran Namasivayam、Antonella Arridu、Jakub Schabikowski、Younis Baqi、Sonja Hinz、Jörg Hockemeyer、Christa E. Müller

  DOI：10.1021/acs.jmedchem.9b00071

  日期：2019.4.25

  The A(2B) adenosine receptor (A(2B)AR) was proposed as a novel target for the (immuno)therapy of cancer since A(2B)AR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A(2B)AR combined with high selectivity. Functional groups were introduced, which will allow the attachment of dyes and other reporter groups. 8-(4((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A(2B)-antagonist (K-i 0.0835 nM, K-B 0.0598 nM, human A(2B)AR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A(2B)AR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.