6-Diethylamino-purin-ribonucleosid | 2139-60-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 6-Diethylamino-purin-ribonucleosid
• 英文别名: 6-Diethylamino-purin ribosid；6-Diethylamino-9-(β-D-ribofuranosyl)purine；(2R,3R,4S,5R)-2-(6-(Diethylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol；(2R,3R,4S,5R)-2-[6-(diethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 2139-60-8
• 化学式: C₁₄H₂₁N₅O₄
• 分子量: 323.352
• InChiKey: AVNJCDRLZOVEDM-IDTAVKCVSA-N

物化性质

• 沸点：
  608.3±65.0 °C(Predicted)
• 密度：
  1.57±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  8

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  6-氯嘌呤核苷	6-Chloropurine riboside	5399-87-1	C10H11ClN4O4	286.675
  肌苷	inosine	58-63-9	C10H12N4O5	268.229
  2,3,5-三-O-乙酰基-6-氯嘌呤-9-β-D-呋喃核糖苷	2',3',5'-O-triacetyl-6-chloroinosine	5987-73-5	C16H17ClN4O7	412.787
  2’,3’,5’-三乙酰肌苷	2',3',5'-tri-O-acetylinosine	3181-38-2	C16H18N4O8	394.341

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	2',3'-(1-methylethylidene)-N6,N-diethyladenosine	109680-71-9	C17H25N5O4	363.417

反应信息

• 作为反应物：
  描述：

  6-Diethylamino-purin-ribonucleosid 在 磷酸三甲酯 、 4-二甲氨基吡啶 、 proton sponge 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 水 、 叔丁醇 为溶剂， 反应 15.5h， 生成 ((2R,3S,4R,5R)-5-(6-(diethylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl (9-(4-methoxy-2-methylphenyl)-3-oxo-3H-xanthen-6-yl) hydrogen phosphate
  参考文献：
  名称：

  靶向肿瘤抑制蛋白 FHIT 的荧光探针的合成和凋亡诱导 FHIT 抑制剂的鉴定

  摘要：

  对于癌症的早期诊断，导致更好的完全康复机会，在癌前病变中表达已经改变的标记基因是可取的，肿瘤抑制基因FHIT是一种候选基因。基因产物 FHIT 蛋白具有独特的二核苷三磷酸水解酶 (AP 3Aase) 活性，在本研究中，我们设计并合成了一系列利用该活性的 FHIT 荧光探针。我们优化了探针结构以实现与 FHIT 的高特异性反应，并将优化的探针应用于 FHIT 抑制剂的筛选试验。用该测定法筛选化合物库确定了几个命中。命中化合物的结构开发提供了有效的 FHIT 抑制剂。这些抑制剂通过半胱天冬酶激活诱导表达 FHIT 的癌症细胞凋亡。我们的结果支持这样的观点，即 FHIT 结合剂，无论是 AP 3 Aase 活性的抑制剂还是激动剂，都可能是有前途的抗癌剂。

  DOI：

  10.1021/acs.jmedchem.1c00874
• 作为产物：
  描述：

  2’,3’,5’-三乙酰肌苷 在 4-二甲氨基吡啶 、 氨 、 三乙胺 、 三氯氧磷 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.84h， 生成 6-Diethylamino-purin-ribonucleosid
  参考文献：
  名称：

  α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors

  摘要：

  ecto-5'-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor alpha,beta-methylene-ADP (AOPCP, adenosine-5'-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N-6-Monosubstitution was superior to symmetrical N-6,N-6-disubstitution. The most potent inhibitors were N-6-(4chlorobenzyl)-(10l, PSB-12441, K-i 7.23 n.M), N-6-phenylethyl(10h, PSB-12425, K-i 8.04 nM), and N-6-benzyl-adenosine-5'-O[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, K-i 9.03 nM). Replacement of the 6-NH group in 10g by 0 (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 aM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nudeotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.

  DOI：

  10.1021/acs.jmedchem.5b00802

文献信息

• Anti-HCV nucleoside derivatives
  申请人：——

  公开号：US20030008841A1

  公开（公告）日：2003-01-09

  The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.

  本发明涉及新颖和已知的嘌呤和嘧啶核苷衍生物，已发现这些衍生物对丙型肝炎病毒（HCV）具有活性。本发明声明利用这些衍生物治疗HCV感染，以及本文所披露的新颖核苷衍生物。
• Nucleotide Analog ARL67156 as a Lead Structure for the Development of CD39 and Dual CD39/CD73 Ectonucleotidase Inhibitors
  作者：Laura Schäkel、Constanze C. Schmies、Riham M. Idris、Xihuan Luo、Sang-Yong Lee、Vittoria Lopez、Salahuddin Mirza、The Hung Vu、Julie Pelletier、Jean Sévigny、Vigneshwaran Namasivayam、Christa E. Müller

  DOI：10.3389/fphar.2020.01294

  日期：——

  compounds’ potency. Selected inhibitors were additionally evaluated in an orthogonal, malachite green assay versus the natural substrate ATP. The most potent CD39 inhibitors of the present series were ARL67156 and its derivatives 31 and 33 with Ki values of around 1 µM. Selectivity studies showed that all three nucleotide analogs additionally blocked CD73 acting as dual-target inhibitors. Docking studies provided

  核苷三磷酸二磷酸水解酶1（NTPDase1，CD39）抑制剂具有作为癌症（免疫）治疗新药的潜力。它们增加了免疫刺激性ATP的细胞外浓度，并减少了AMP的形成，后者可以被ecto-5'-核苷酸酶（CD73）进一步水解为免疫抑制，促进癌症的腺苷。在本研究中，我们合成了标准CD39抑制剂ARL67156的类似物和衍生物，这是一种显示出竞争性抑制机制的核苷酸类似物。在人酶处分析了结构-活性之间的关系。ñ腺嘌呤核的6-和C8-位，以及三磷酸（on）酸酯链的修饰。使用荧光标记的ATP衍生物的毛细管电泳与激光诱导的荧光检测耦合，以确定化合物的效力。相对于天然底物ATP，还通过正交的孔雀石绿分析法评估了选定的抑制剂。本系列中最有效的CD39抑制剂是ARL67156及其衍生物31和33ķ我值约为1 µM。选择性研究表明，所有三个核苷酸类似物还阻断了CD73作为双重靶标抑制剂的作用。对接研究为两个靶标提供了可
• Testing Nucleoside Analogues as Inhibitors of <i>Bacillus anthracis</i> Spore Germination <i>In Vitro</i> and in Macrophage Cell Culture
  作者：Zadkiel Alvarez、Kyungae Lee、Ernesto Abel-Santos

  DOI：10.1128/aac.01029-10

  日期：2010.12

  Bacillus anthracis , the etiological agent of anthrax, has a dormant stage in its life cycle known as the endospore. When conditions become favorable, spores germinate and transform into vegetative bacteria. In inhalational anthrax, the most fatal manifestation of the disease, spores enter the organism through the respiratory tract and germinate in phagosomes of alveolar macrophages. Germinated cells can then produce toxins and establish infection. Thus, germination is a crucial step for the initiation of pathogenesis. B. anthracis spore germination is activated by a wide variety of amino acids and purine nucleosides. Inosine and l -alanine are the two most potent nutrient germinants in vitro . Recent studies have shown that germination can be hindered by isomers or structural analogues of germinants. 6-Thioguanosine (6-TG), a guanosine analogue, is able to inhibit germination and prevent B. anthracis toxin-mediated necrosis in murine macrophages. In this study, we screened 46 different nucleoside analogues as activators or inhibitors of B. anthracis spore germination in vitro . These compounds were also tested for their ability to protect the macrophage cell line J774a.1 from B. anthracis cytotoxicity. Structure-activity relationship analysis of activators and inhibitors clarified the binding mechanisms of nucleosides to B. anthracis spores. In contrast, no structure-activity relationships were apparent for compounds that protected macrophages from B. anthracis -mediated killing. However, multiple inhibitors additively protected macrophages from B. anthracis .

  摘要 炭疽杆菌 炭疽杆菌是炭疽病的病原体，在其生命周期中有一个称为内生孢子的休眠阶段。当条件有利时，孢子发芽并转化为无性繁殖细菌。在吸入性炭疽这种最致命的疾病中，孢子通过呼吸道进入机体，并在肺泡巨噬细胞的吞噬体中发芽。发芽的细胞随后可产生毒素并形成感染。因此，发芽是启动致病机制的关键步骤。 炭疽杆菌 孢子萌发是由多种氨基酸和嘌呤核苷激活的。肌苷和 l -丙氨酸是两种最有效的营养萌发剂 体外 .最近的研究表明，萌芽剂的异构体或结构类似物会阻碍萌芽。6-Thioguanosine (6-TG)是一种鸟苷类似物，能够抑制萌芽并防止炭疽杆菌的萌发。 炭疽杆菌 毒素介导的小鼠巨噬细胞坏死。在这项研究中，我们筛选了 46 种不同的核苷类似物作为炭疽杆菌毒素的激活剂或抑制剂。 炭疽杆菌 孢子萌发 体外 .我们还测试了这些化合物保护巨噬细胞系 J774a.1 免受炭疽杆菌感染的能力。 炭疽杆菌 细胞毒性的能力。激活剂和抑制剂的结构-活性关系分析阐明了核苷与炭疽杆菌的结合机制。 炭疽杆菌 孢子的结合机制。与此相反，保护巨噬细胞免受炭疽杆菌侵袭的化合物却没有明显的结构-活性关系。 炭疽杆菌 -介导的杀灭。然而，多种抑制剂相加可保护巨噬细胞免受 炭疽杆菌 .
• 2-Hexylthio-β,γ-CH₂-ATP is an Effective and Selective NTPDase2 Inhibitor
  作者：Irina Gillerman、Joanna Lecka、Luba Simhaev、Mercedes N. Munkonda、Michel Fausther、Mireia Martín-Satué、Hanoch Senderowitz、Jean Sévigny、Bilha Fischer

  DOI：10.1021/jm401933c

  日期：2014.7.24

  NTPDase2 catabolizes nucleoside triphosphates and consequently, through the interaction of nucleotides with P2 receptors, controls multiple biological responses. NTPDase2 inhibitors could modulate responses induced by nucleotides in thrombosis, inflammation, cancer, etc. Here we developed a set of ATP analogues as potential NTPDase inhibitors and identified a subtype-selective and potent NTPDase2 inhibitor, 2-hexylthio-beta,gamma-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with K-i 20 mu M, while only marginally (5-15%) inhibiting NTPDase1, -3, and -8. Homology models of hNTPDase1 and -2 were constructed. Docking and subsequent linear interaction energy (LIE) simulations provided a correlation with r(2) = 0.94 between calculated and experimental inhibition data for the triphosphate analogues considered in this work. The origin of selectivity of 2 for NTPDase2 over NTPDase1 is the thiohexyl moiety of 2 which is favorably located within a hydrophobic pocket, whereas in NTPDase1 it is exposed to the solvent.
• NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF HEPATITIS C
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP1315736A2

  公开（公告）日：2003-06-04