bromo-deaza-SAH | 1428254-21-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: bromo-deaza-SAH
• 英文别名: (2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid
• CAS: 1428254-21-0
• 化学式: C₁₅H₂₀BrN₅O₅S
• 分子量: 462.324
• InChiKey: DIULHULFPSIBAK-TWBCTODHSA-N

物化性质

• 沸点：
  801.9±65.0 °C(predicted)
• 密度：
  2.05±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  195
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  L-高半胱氨酸 、 (2R,3R,4R,5R)-2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(chloromethyl)tetra-hydrofuran-3,4-diol 在 potassium iodide 、 sodium hydroxide 作用下， 以 水 为溶剂， 反应 2.0h， 以9%的产率得到bromo-deaza-SAH
  参考文献：
  名称：

  Bromo-deaza-SAH: A potent and selective DOT1L inhibitor

  摘要：

  Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.01.049

文献信息

• Bromo-deaza-SAH: A potent and selective DOT1L inhibitor
  作者：Wenyu Yu、David Smil、Fengling Li、Wolfram Tempel、Oleg Fedorov、Kong T. Nguyen、Yuri Bolshan、Rima Al-Awar、Stefan Knapp、Cheryl H. Arrowsmith、Masoud Vedadi、Peter J. Brown、Matthieu Schapira

  DOI：10.1016/j.bmc.2013.01.049

  日期：2013.4

  Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia. (C) 2013 Elsevier Ltd. All rights reserved.