ethyl (E)-3-{(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl}prop-2-enoate | 102044-62-2

• 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: ethyl (E)-3-{(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl}prop-2-enoate
• 英文别名: ethyl(E)-3-((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylate；1-(6-amino-purin-9-yl)-O²,O³-isopropylidene-β-D-ribo-1,5,6-trideoxy-hept-5-enofuranuronic acid ethyl ester；ethyl (E)-3-[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]prop-2-enoate
• CAS: 102044-62-2
• 化学式: C₁₇H₂₁N₅O₅
• 分子量: 375.384
• InChiKey: QQQGOMQXBFPGKP-KBMGPZOWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ethyl (E)-3-{(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl}prop-2-enoate 在 二异丁基氢化铝 、 三苯基膦 、 甲胺 、 三氟乙酸 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 为溶剂， 反应 37.5h， 生成 2-(3-aminopropenyl)-5-(6-aminopurin-9-yl)tetrahydrofuran-3,4-diol
  参考文献：
  名称：

  Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity

  摘要：

  抑制儿茶酚-O-甲基转移酶(COMT)是治疗帕金森病的重要方法。根据基于X射线结构设计的原理，一系列新型强效双底物COMT抑制剂已被合成，这些抑制剂具有腺苷和儿茶酚结构单元。生物学结果显示，结合亲和力对抑制剂的预组织结构及核苷与儿茶酚单元间连接链的长度有较大依赖性。对COMT最有效的双底物抑制剂的IC50值为9 nM。它对SAM结合位点表现出竞争性动力学特性，而对儿茶酚结合位点则呈现出混合抑制动力学特征。其双底物结合模式通过分析抑制剂、COMT及Mg2+离子形成的三元复合物的X射线结构得到确认。

  DOI：

  10.1039/b208690p
• 作为产物：
  描述：

  腺苷 在 高氯酸 、 2-碘酰基苯甲酸 作用下， 以 二甲基亚砜 为溶剂， 反应 77.0h， 生成 ethyl (E)-3-{(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethylperhydrofuro[3,4-d][1,3]dioxol-4-yl}prop-2-enoate
  参考文献：
  名称：

  通过解构-重建和片段生长方法将 I 型蛋白精氨酸甲基转移酶的非选择性抑制剂转化为蛋白精氨酸甲基转移酶 4 的有效和选择性抑制剂

  摘要：

  蛋白质精氨酸甲基转移酶 (PRMT) 是重要的治疗靶点，在许多细胞过程的调节中起着至关重要的作用，并与许多疾病有关。然而，关于它们的功能和它们所涉及的生物学途径，以及可能推动 PRMT 活性选择性调节剂发展的结构要求，仍有许多有待了解。在这里，我们报告了一种解构-重建方法，该方法从我们之前鉴定的一系列 I 型 PRMT 抑制剂开始，允许鉴定 PRMT4 的有效和选择性抑制剂，无论细胞渗透性低如何，都显示精氨酸甲基化明显减少MCF7 细胞中的水平和增殖的显着减少。

  DOI：

  10.1021/acs.jmedchem.2c00252

文献信息

• Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites
  作者：Matthijs van Haren、Linda Quarles van Ufford、Ed E. Moret、Nathaniel I. Martin

  DOI：10.1039/c4ob01734j

  日期：——

  transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases

  蛋白质精氨酸N-甲基转移酶（PRMT）是一类酶，其作用是通过从辅助因子S-腺苷基L特异性转移甲基来发挥功能-甲硫氨酸（AdoMet）修饰靶蛋白中精氨酸残基的胍基。最值得注意的是组蛋白中存在的PRMT介导的精氨酸残基甲基化，可导致染色质重塑并影响基因转录。现在越来越多的证据表明PRMT活性失调可能导致多种疾病，包括各种形式的癌症。因此，PRMT抑制剂的开发可能具有开发新疗法的潜力。我们在此报告了一系列小分子PRMT抑制剂的合成和评估，这些抑制剂旨在同时占据胍基底物和AdoMet辅因子的结合位点。当针对一组甲基转移酶测试这些化合物时，观察到有效的抑制作用和令人惊讶的选择性。
• New COMT inhibitors for the treatment of depression and impaired cognition
  申请人：Diederich Francois

  公开号：US20050137162A1

  公开（公告）日：2005-06-23

  The present invention relates to compounds of formula I wherein R 1 is as defined in the specification and to esters thereof which are hydrolyzable under physiological conditions and to the pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of COMT and, thus, are useful for the treatment of diseases for which COMT inhibition is beneficial. The invention further relates to the treatment, control, or prevention of diseases such as depression, schizophrenia, Parkinson's disease, and to improve cognition.

  本发明涉及以下式I的化合物 其中R 1 如规范中定义 以及在生理条件下可水解的酯及其药用可接受的盐。本发明的化合物是COMT的抑制剂，因此对于COMT抑制有益的疾病的治疗是有用的。本发明还涉及治疗、控制或预防抑郁症、精神分裂症、帕金森病以及改善认知的疾病。
• An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
  作者：Jonathan Pettinger、Yann‐Vaï Le Bihan、Marcella Widya、Rob L. M. van Montfort、Keith Jones、Matthew D. Cheeseman

  DOI：10.1002/anie.201611907

  日期：2017.3.20

  chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine‐targeted irreversible inhibitor. Using rational

  应激诱导的分子伴侣HSP72是肿瘤学中的重要治疗靶标，但是用小分子抑制该蛋白已证明是特别具有挑战性的。由于与其内源核苷酸底物的高亲和力和竞争性竞争，很难在细胞中验证HSP72抑制剂。我们假设使用半胱氨酸靶向的不可逆抑制剂可以克服这一问题。通过合理的设计，我们将经过验证的8‐ N‐苄基腺苷配体用于共价键形成，并确定了靶向的不可逆抑制作用。但是，该蛋白质中的半胱氨酸没有被修饰。相反，我们证明了赖氨酸56是关键的亲核残基。针对这种赖氨酸可能会导致针对HSP72化学探针和药物的新设计范例。
• Toward the synthesis of isozyme-specific enzyme inhibitors. Potent inhibitors of rat methionine adenosyltransferases. Effect of one-atom elongation of the ribose-P.alpha. bridge in two covalent adducts of L-methionine and .beta.,.gamma.-imido-ATP
  作者：Francis Kappler、Vivekananda M. Vrudhula、Alexander Hampton

  DOI：10.1021/jm00397a020

  日期：1988.2

  With 2',3'-O-isopropylideneadenosine or its N6-benzoyl derivative as starting material, synthetic routes to two novel adducts of L-methionine and beta,gamma-imido-ATP have been devised. One adduct, 14 (2:3 mixture of 6' epimers), had a P alpha OCH(R1)CH2 system [R1 = CH2-L-SCH2CH2CH2CH(NH2)CO2H] in place of the P alpha OC(5')H2 system of ATP, while the other, 16 (2:3 mixture of 5' epimers), had a P alpha OCH2CH2CH(R2) system [R2 = L-SCH2CH2CH(NH2)CO2H]. The ribose-P alpha bridge in 14 and 16 contained one more methylene group than in two homologous methionine-ATP adducts studied previously. Adduct 14 was a potent inhibitor of the rat M-2 (normal tissue) and M-T (Novikoff ascitic hepatoma) variants of methionine adenosyltransferase and gave competitive kinetics vs MgATP (Ki = 0.39 and 0.63 microM, respectively) or vs L-methionine (Ki = 2.2 and 2.7 microM). Adduct 16 was likewise a potent inhibitor competitive vs MgATP (Ki = 0.44 and 0.81 microM, respectively) or L-methionine (Ki = 2.1 and 1.5 microM). The kinetic data indicate that 14 and 16 inhibit by binding simultaneously to the MgATP and L-methionine substrate sites and that the extra methylene group facilitates the interaction of their methionine residues with these methionine sites.
• X-ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol-O-methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding Affinity We thank F. Hoffmann–La Roche for generous support of this work. We are grateful to P. Malherbe for the cloning of COMT, P. Caspers for the expression of COMT, A. Cesura for enzyme purification, B. Wipf for fermentation, and H. W. Lahm for sequencing.
  作者：Christian Lerner、Armin Ruf、Volker Gramlich、Birgit Masjost、Gerhard Zürcher、Roland Jakob-Roetne、Edilio Borroni、François Diederich

  DOI：10.1002/1521-3773(20011105)40:21<4040::aid-anie4040>3.0.co;2-c

  日期：2001.11.5

  With an IC50 value of 9 nM, 1 is the most potent known disubstrate inhibitor for catechol-O-methyltransferase (COMT). Inhibition of COMT is of significant interest in the therapy of Parkinsonapos;s disease since it ensures that a larger percentage of orally administered L-dopa reaches-in the form of dopamine-its target in the brain. The X-ray crystal structure of a complex formed by COMT and 1 has been solved at 2.6-Å resolution.