2-amino-6-chloro-9-(cyclohexyl)-9H-purine | 247193-35-7

• 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: 2-amino-6-chloro-9-(cyclohexyl)-9H-purine
• 英文别名: 6-Chloro-9-cyclohexylpurin-2-amine
• CAS: 247193-35-7
• 化学式: C₁₁H₁₄ClN₅
• 分子量: 251.719
• InChiKey: RZEQFAFEEQPYQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 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：
  69.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-6-chloro-9-(cyclohexyl)-9H-purine 在 氟化氢吡啶 、 N,N-二异丙基乙胺 、 亚硝酸异戊酯 作用下， 以 正丁醇 为溶剂， 反应 12.08h， 生成 C₂₀H₂₅FN₆O₃S
  参考文献：
  名称：

  基于降冰片基的碳环核苷类似物作为细胞周期蛋白依赖性激酶 2 抑制剂的优化。

  摘要：

  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。

  DOI：

  10.1002/jmr.2842
• 作为产物：
  描述：

  环己胺 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 水 、 正丁醇 为溶剂， 反应 24.0h， 生成 2-amino-6-chloro-9-(cyclohexyl)-9H-purine
  参考文献：
  名称：

  用于靶向自噬降解的第二代 AUTAC

  摘要：

  通过泛素-蛋白酶体系统进行的靶向蛋白质降解已成为最有前途的药物发现方式之一。自噬是另一种细胞内降解系统，可以靶向多种非蛋白质底物以及蛋白质，但其在靶向降解中的应用仍处于起步阶段。我们之前的工作揭示了细胞内蛋白质上半胱氨酸残基的鸟嘌呤修饰与选择性自噬之间的关系，从而产生了第一个基于自噬的降解剂，即自噬靶向嵌合体（AUTAC）。基于研究背景，所有报道的AUTACs化合物都含有半胱氨酸作为子结构。在这里，我们通过进行 SAR 研究来检查该子结构的重要性，并报告通过用其他部分替换半胱氨酸来显着改善降解剂的活性。几种衍生物表现出亚μM范围的降解活性，证明了AUTAC增加的实用价值。

  DOI：

  10.1021/acs.jmedchem.3c00861

文献信息

• Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1
  作者：Tushar Mahajan、Mari Ytre-Arne、Pernille Strøm-Andersen、Bjørn Dalhus、Lise-Lotte Gundersen

  DOI：10.3390/molecules200915944

  日期：——

  The human 8-oxoguanine DNA glycosylase OGG1 is involved in base excision repair (BER), one of several DNA repair mechanisms that may counteract the effects of chemo- and radiation therapy for the treatment of cancer. We envisage that potent inhibitors of OGG1 may be found among the 9-alkyl-8-oxoguanines. Thus we explored synthetic routes to 8-oxoguanines and examined these as OGG1 inhibitors. The best reaction sequence started from 6-chloroguanine and involved N-9 alkylation, C-8 bromination, and finally simultaneous hydrolysis of both halides. Bromination before N-alkylation should only be considered when the N-substituent is not compatible with bromination conditions. The 8-oxoguanines were found to be weak inhibitors of OGG1. 6-Chloro-8-oxopurines, byproducts in the hydrolysis of 2,6-halopurines, turned out to be slightly better inhibitors than the corresponding 8-oxoguanines.

  人类 8-氧代鸟嘌呤 DNA 糖基化酶 OGG1 参与碱基切除修复（BER），BER 是几种 DNA 修复机制之一，可以抵消化疗和放疗对癌症治疗的影响。我们设想，可能会在 9-烷基-8-氧代鸟嘌呤中发现有效的 OGG1 抑制剂。因此，我们探索了 8-氧代鸟嘌呤的合成路线，并将其作为 OGG1 抑制剂进行研究。最佳的反应顺序是从 6-氯鸟嘌呤开始，包括 N-9 烷基化、C-8 溴化，最后同时水解两种卤化物。只有当 N-取代基不符合溴化条件时，才应考虑在 N-烷基化之前进行溴化。研究发现，8-氧代鸟嘌呤是 OGG1 的弱抑制剂。2,6-卤代嘌呤水解过程中产生的副产物 6-氯-8-氧代嘌呤的抑制效果略好于相应的 8-氧代鸟嘌呤。
• Synthesis and in vitro evaluation of novel 2,6,9-trisubstituted purines acting as cyclin-dependent kinase inhibitors
  作者：Michel Legraverend、Odile Ludwig、Emile Bisagni、Sophie Leclerc、Laurent Meijer、Nicole Giocanti、Ramin Sadri、Vincent Favaudon

  DOI：10.1016/s0968-0896(99)00064-4

  日期：1999.7

  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.