8-[2-(hydroxymethyl)phenylsulfanyl]adenine

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 8-[2-(hydroxymethyl)phenylsulfanyl]adenine
• 英文别名: 8-(2-hydroxymethyl-phenylsulfanyl)adenine；[2-[(6-amino-7H-purin-8-yl)sulfanyl]phenyl]methanol
• 化学式: C₁₂H₁₁N₅OS
• 分子量: 273.318
• InChiKey: URJORMIUDFIMSL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  戊-4-炔基对甲苯磺酸酯 、 8-[2-(hydroxymethyl)phenylsulfanyl]adenine 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以56%的产率得到[2-(6-Amino-9-pent-4-ynyl-9H-purin-8-ylsulfanyl)-phenyl]-methanol
  参考文献：
  名称：

  Evaluation of 8-Arylsulfanyl, 8-Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90

  摘要：

  Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC50 = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.

  DOI：

  10.1021/jm049012b
• 作为产物：
  描述：

  2-碘苄醇 、 8-巯基腺嘌呤 在 copper(l) iodide 、 新铜试剂 sodium t-butanolate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以79%的产率得到8-[2-(hydroxymethyl)phenylsulfanyl]adenine
  参考文献：
  名称：

  合成8-芳基硫烷基腺嘌呤衍生物的通用方法

  摘要：

  我们报告了使用8-巯基腺嘌呤与各种芳基碘偶联的温和协议合成8-芳基硫烷基腺嘌呤衍生物的一般方法。

  DOI：

  10.1021/jo049875c

文献信息

• General Method for the Synthesis of 8-Arylsulfanyl Adenine Derivatives
  作者：Huazhong He、Laura Llauger、Neal Rosen、Gabriela Chiosis

  DOI：10.1021/jo049875c

  日期：2004.4.1

  We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides.

  我们报告了使用8-巯基腺嘌呤与各种芳基碘偶联的温和协议合成8-芳基硫烷基腺嘌呤衍生物的一般方法。
• Structure–Activity Relationship in a Purine-Scaffold Compound Series with Selectivity for the Endoplasmic Reticulum Hsp90 Paralog Grp94
  作者：Hardik J. Patel、Pallav D. Patel、Stefan O. Ochiana、Pengrong Yan、Weilin Sun、Maulik R. Patel、Smit K. Shah、Elisa Tramentozzi、James Brooks、Alexander Bolaender、Liza Shrestha、Ralph Stephani、Paola Finotti、Cynthia Leifer、Zihai Li、Daniel T. Gewirth、Tony Taldone、Gabriela Chiosis

  DOI：10.1021/acs.jmedchem.5b00197

  日期：2015.5.14

  Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 mu M) and selectivity over other paralogs (>100- and 33-fold for Hsp90 alpha/beta and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.
• Evaluation of 8-Arylsulfanyl, 8-Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90
  作者：Laura Llauger、Huazhong He、Joungnam Kim、Julia Aguirre、Neal Rosen、Ulf Peters、Peter Davies、Gabriela Chiosis

  DOI：10.1021/jm049012b

  日期：2005.4.1

  Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC50 = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.