5'-[2-(amino)ethylthio]-5'-deoxyadenosine | 38716-43-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 5'-脱氧核糖核苷
• 英文名称: 5'-[2-(amino)ethylthio]-5'-deoxyadenosine
• 英文别名: (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-(((2-aminoethyl)thio)methyl)tetrahydrofuran-3,4-diol；5′-(2-aminoethyl)thio-5′-deoxyadenosine；5'-aminoethylthioadenosine；5'-Desoxy-5'-<2-amino-aethylmercapto>-adenosin；S-(2-amino-ethyl)-5'-thio-adenosine；5'-S-Adenosyl-cysteamin；5'-Deoxy-5'-[2-(amino)ethylthio]adenosine；(2S,3S,4R,5R)-2-(2-aminoethylsulfanylmethyl)-5-(6-aminopurin-9-yl)oxolane-3,4-diol
• CAS: 38716-43-7
• 化学式: C₁₂H₁₈N₆O₃S
• 分子量: 326.379
• InChiKey: APAPOJUCRZTCHD-WOUKDFQISA-N

物化性质

• 沸点：
  684.5±65.0 °C(Predicted)
• 密度：
  1.87±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  171
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5'-[2-(amino)ethylthio]-5'-deoxyadenosine 生成 N-[2-[[(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(4-nitrophenyl)methylamino]purin-9-yl]oxolan-2-yl]methylsulfanyl]ethyl]acetamide
  参考文献：
  名称：

  AGBANYO, FRANCISCA R.;VIJAYALAKSHMI, DAMARAJU;CRAIK, JAMES D.;GATI, WENDY+, BIOCHEM. J., 270,(1990) N, C. 605-614

  摘要：

  DOI：
• 作为产物：
  描述：

  腺苷 在 吡啶 、 氯化亚砜 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 0.5h， 生成 5'-[2-(amino)ethylthio]-5'-deoxyadenosine
  参考文献：
  名称：

  组蛋白甲基转移酶DOT1L含腺苷抑制剂的合成及构效关系研究

  摘要：

  组蛋白 3-赖氨酸 79 (H3K79) 甲基转移酶 DOT1L 已被发现是具有 MLL（混合谱系白血病）基因易位的急性白血病的药物靶点。总共设计和合成了 55 种含腺苷的化合物，其中鉴定了几种有效的 DOT1L 抑制剂，K i值低至 0.5 nM。与其他三种组蛋白甲基转移酶相比，这些化合物还显示出高选择性（> 4500 倍）。讨论了这些化合物对 DOT1L 的抑制活性的构效关系 (SAR)。强效 DOT1L 抑制剂对 MLL 易位白血病细胞系 MV4;11 和 THP1 的增殖具有选择性活性，EC 504–11 μM 的值。等温滴定量热研究表明，两种代表性抑制剂以高亲和力与 DOT1L:核小体复合物结合，仅与酶辅因子 SAM（S-腺苷-1-甲硫氨酸）竞争，而不与底物核小体竞争。

  DOI：

  10.1021/jm300917h

文献信息

• Inhibitors of DNA Methyltransferase
  申请人：Wahhab Amal

  公开号：US20080132525A1

  公开（公告）日：2008-06-05

  The invention relates to the inhibition of DNA methyltransferase isoforms DNMT1 and DNMT3b2. The invention provides compounds and methods for inhibiting DNMT1 and DNMT3b2.

  这项发明涉及抑制DNA甲基转移酶亚型DNMT1和DNMT3b2。该发明提供了用于抑制DNMT1和DNMT3b2的化合物和方法。
• Structure-Based Drug Design of Bisubstrate Inhibitors of Phenylethanolamine <i>N</i>-Methyltransferase Possessing Low Nanomolar Affinity at Both Substrate Binding Domains¹
  作者：Jian Lu、Aaron G. Bart、Qian Wu、Kevin R. Criscione、Michael J. McLeish、Emily E. Scott、Gary L. Grunewald

  DOI：10.1021/acs.jmedchem.0c01475

  日期：2020.11.25

  pharmacology. A bisubstrate analogue approach offers the potential for development of highly selective inhibitors of PNMT. This paper documents the design, synthesis, and evaluation of such analogues, several of which were found to possess human PNMT (hPNMT) inhibitory potency <5 nM versus AdoMet. Site-directed mutagenesis studies were consistent with bisubstrate binding. Two of these compounds (19

  苯乙醇胺N-甲基转移酶 (PNMT, EC 2.1.1.28) 催化肾上腺素生物合成的最后一步，是一种潜在的药物靶点，主要用于控制高血压。不幸的是，许多有效的 PNMT 抑制剂也对2 -肾上腺素受体具有显着的亲和力，这使对其药理学的解释复杂化。双底物类似物方法为开发高选择性 PNMT 抑制剂提供了潜力。本文记录了此类类似物的设计、合成和评估，其中一些被发现具有与 AdoMet 相比 <5 nM 的人类 PNMT (hPNMT) 抑制效力。定点诱变研究与双底物结合一致。其中两种化合物（19和29 ) 与 hPNMT 共结晶，所得结构显示两种化合物如预测的那样结合，同时占据两个底物结合结构域。这种双底物抑制剂方法已经产生了迄今为止报道的最有效（20）和选择性（相对于α 2-肾上腺素受体）的 hPNMT 抑制剂之一。
• Combination therapies for treating methylthioadenosine phosphorylase deficient cells
  申请人：——

  公开号：US20040043959A1

  公开（公告）日：2004-03-04

  The present invention is directed to combination therapies for treating cell proliferative disorders associated with methylthioadenosine phosphorylase (MTAP) deficient cells in a mammal. The combination therapies selectively kill MTAP-deficient cells by administering an inhibitor of de novo inosinate synthesis and administering an anti-toxicity agent, wherein the inhibitors of de novo inosinate synthesis are inhibitors of glycinamide ribonucleotide formyltransferase (“GARFT”) and/or aminoinidazolecarboximide ribonucleotide formyltransferase (“AICARFT”), and the anti-toxicity agent is an MTAP substrate (e.g. methylthioadenosine or “MTA”), a precursor of MTA, an analog of an MTA precursor or a prodrug of an MTAP substrate.

  本发明涉及用于治疗哺乳动物中与甲基硫腺苷磷酸化酶（MTAP）缺乏细胞相关的细胞增殖性疾病的联合疗法。该联合疗法通过给予新生核苷酸合成抑制剂和给予抗毒性剂，选择性地杀死MTAP缺乏细胞，其中，新生核苷酸合成抑制剂是甘氨酰核苷酸甲酰转移酶（“GARFT”）和/或氨基咪唑羧酰核苷酸甲酰转移酶（“AICARFT”）的抑制剂，抗毒性剂是MTAP底物（例如，甲基硫腺苷或“MTA”），MTA的前体，MTA前体的类似物或MTAP底物的前药。
• Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors
  作者：Ljubomir Isakovic、Oscar M. Saavedra、David B. Llewellyn、Stephen Claridge、Lijie Zhan、Naomy Bernstein、Arkadii Vaisburg、Nadine Elowe、Andrea J. Petschner、Jubrail Rahil、Norman Beaulieu、France Gauthier、A. Robert MacLeod、Daniel Delorme、Jeffrey M. Besterman、Amal Wahhab

  DOI：10.1016/j.bmcl.2009.03.132

  日期：2009.5

  Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity pro. le of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N-6 alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N-6 positions reduced activity against both enzymes. (C) 2009 Elsevier Ltd. All rights reserved.
• Discovery of a Dual PRMT5–PRMT7 Inhibitor
  作者：David Smil、Mohammad S. Eram、Fengling Li、Steven Kennedy、Magdalena M. Szewczyk、Peter J. Brown、Dalia Barsyte-Lovejoy、Cheryl H. Arrowsmith、Masoud Vedadi、Matthieu Schapira

  DOI：10.1021/ml500467h

  日期：2015.4.9

  The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. Using available structures of PRMT5, we designed DS-437, a PRMT5 inhibitor with an IC50 value of 6 mu M against both PRMT5 and PRMT7 that is inactive against 29 other human protein-, DNA-, and RNA-methyltransferases and inhibits symmetrical dimethylation of PRMT5 substrates in cells. This compound behaves as a cofactor competitor and represents a valid scaffold to interrogate the potential of the PRMT5-PRMT7 axis as a target for therapy.