6-chloro-2-iodo-9-cyclohexyl-9H-purine | 247193-38-0

• 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: 6-chloro-2-iodo-9-cyclohexyl-9H-purine
• 英文别名: 6-chloro-9-cyclohexyl-2-iodo-9H-purine；6-Chloro-9-cyclohexyl-2-iodopurine
• CAS: 247193-38-0
• 化学式: C₁₁H₁₂ClIN₄
• 分子量: 362.601
• InChiKey: IWHBAJIEOYLMGZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-2-iodo-9-cyclohexyl-9H-purine 在 三正丙胺 、 三乙胺 作用下， 以 乙醇 、 N,N-二甲基乙酰胺 为溶剂， 反应 27.0h， 生成 2,6,9-Trisubstituted purine deriv. 23
  参考文献：
  名称：

  Synthesis and in vitro evaluation of novel 2,6,9-trisubstituted purines acting as cyclin-dependent kinase inhibitors

  摘要：

  Novel C-2, C-6, N-9 trisubstituted purines derived from the olomoucine/roscovitine lead structure were synthesized and evaluated for their ability to inhibit starfish oocyte CDK1/cyclin B, neuronal CDK5/p35 and erk1 kinases in purified extracts. Structure-activity relationship studies showed that increased steric bulk at N-9 reduces the inhibitory potential whereas substitution of the aminoethanol C-2 side chain by various groups of different size (methyl, propyl, butyl, phenyl, benzyl) only slightly decreases the activity when compared to (R)-roscovitine. Optimal inhibitory activity against CDK5, CDK1 and CDK2, with IC50 values of 0.16, 0.45 and 0.65 mu M, respectively, was obtained with compound 21 containing a (2R)-pyrrolidin-2-yl-methanol substituent at the C-2 and a 3-iodobenzylamino group at the C-6 of the purine. Compound 21 proved cytotoxic against human tumor HeLa cells (LD50 = 6.7 mu M versus 42.7 mu M for olomoucine, 24-h contact). Furthermore, unlike olomoucine, compound 21 was effective upon short exposure (LD50 = 25.3 mu M, 2-h contact). The available data suggest that the affinity for CDKs and the cytotoxic potential of the drugs are inter-related. However, no straightforward cell cycle phase specificity of the cytotoxic response to 21 was observed in synchronized HeLa cells. With the noticeable exception of pronounced lengthening of the S-phase transit by 21 applied during early-S in synchronized HeLa cells, and in striking contrast with earlier reports on studies using plant or echinoderm cells, olomoucine and compound 21 were unable to reversibly arrest cell cycle progression in asynchronous growing HeLa cells. Some irreversible block in G1 and G2 phase occurred at high olomoucine concentration, correlated with induced cell death. Moreover, chronic exposure to lethal doses of compound 21 resulted in massive nuclear fragmentation, evocative of mitotic catastrophe with minor amounts of apoptosis only. It was also found that olomoucine and compound 21 reversibly block the intracellular uptake of nucleosides with high efficiency. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00064-4
• 作为产物：
  描述：

  6-chloro-N4-cyclohexylpyrimidine-2,4,5-triamine 在 盐酸 、 copper(l) iodide 、 二碘甲烷 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 为溶剂， 生成 6-chloro-2-iodo-9-cyclohexyl-9H-purine
  参考文献：
  名称：

  Synthesis and in vitro evaluation of novel 2,6,9-trisubstituted purines acting as cyclin-dependent kinase inhibitors

  摘要：

  Novel C-2, C-6, N-9 trisubstituted purines derived from the olomoucine/roscovitine lead structure were synthesized and evaluated for their ability to inhibit starfish oocyte CDK1/cyclin B, neuronal CDK5/p35 and erk1 kinases in purified extracts. Structure-activity relationship studies showed that increased steric bulk at N-9 reduces the inhibitory potential whereas substitution of the aminoethanol C-2 side chain by various groups of different size (methyl, propyl, butyl, phenyl, benzyl) only slightly decreases the activity when compared to (R)-roscovitine. Optimal inhibitory activity against CDK5, CDK1 and CDK2, with IC50 values of 0.16, 0.45 and 0.65 mu M, respectively, was obtained with compound 21 containing a (2R)-pyrrolidin-2-yl-methanol substituent at the C-2 and a 3-iodobenzylamino group at the C-6 of the purine. Compound 21 proved cytotoxic against human tumor HeLa cells (LD50 = 6.7 mu M versus 42.7 mu M for olomoucine, 24-h contact). Furthermore, unlike olomoucine, compound 21 was effective upon short exposure (LD50 = 25.3 mu M, 2-h contact). The available data suggest that the affinity for CDKs and the cytotoxic potential of the drugs are inter-related. However, no straightforward cell cycle phase specificity of the cytotoxic response to 21 was observed in synchronized HeLa cells. With the noticeable exception of pronounced lengthening of the S-phase transit by 21 applied during early-S in synchronized HeLa cells, and in striking contrast with earlier reports on studies using plant or echinoderm cells, olomoucine and compound 21 were unable to reversibly arrest cell cycle progression in asynchronous growing HeLa cells. Some irreversible block in G1 and G2 phase occurred at high olomoucine concentration, correlated with induced cell death. Moreover, chronic exposure to lethal doses of compound 21 resulted in massive nuclear fragmentation, evocative of mitotic catastrophe with minor amounts of apoptosis only. It was also found that olomoucine and compound 21 reversibly block the intracellular uptake of nucleosides with high efficiency. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00064-4

文献信息

• Optimization of norbornyl‐based carbocyclic nucleoside analogs as cyclin‐dependent kinase 2 inhibitors
  作者：Cemal Köprülüoğlu、Milan Dejmek、Michal Šála、Haresh Ajani、Hubert Hřebabecký、Jindřich Fanfrlík、Radek Jorda、Martin Dračínský、Eliška Procházková、Pavel Šácha、Vladimír Kryštof、Pavel Hobza、Martin Lepšík、Radim Nencka

  DOI：10.1002/jmr.2842

  日期：2020.8

  explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting

  我们报告了降冰片基部分作为细胞周期蛋白依赖性激酶 2 (CDK2) 抑制剂的新型结构基序的发现，该基序是通过筛选碳环核苷类似物文库确定的。通过使用药物化学方法将三个微摩尔命中扩展为一系列 16 种新化合物。它们对 CDK2 具有显着的微摩尔活性，并且该系列中最好的化合物达到了 IC 50190 纳米。通过建模和对接在分子细节中探索结合模式。使用基于量子力学的评分来合理化亲和力。总之，所发现的 9-羟甲基降冰片基部分通过联合实验-理论努力表明能够作为 CDK2 抑制剂的新取代基。这一发现为探索化学空间以寻找更有效的靶向这一类重要蛋白激酶的衍生物打开了大门。