NU6034 | 220036-14-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: NU6034
• 英文别名: 6-(cyclohexylmethoxy)pyrimidine-2,4-diamine；4-cyclohexylmethoxy-2,6-diaminopyrimidine；DR193；2,6-diamino-4-cyclohexylmethoxypyrimidine
• CAS: 220036-14-6
• 化学式: C₁₁H₁₈N₄O
• 分子量: 222.29
• InChiKey: HFTATNPBYYGATN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  NU6034 在 溶剂黄146 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 0.83h， 以60%的产率得到6-二氨基-5-亚硝基嘧啶
  参考文献：
  名称：

  NU-6027通过靶向蛋白激酶D和蛋白激酶G抑制结核分枝杆菌的生长。

  摘要：

  结核病（TB）是一个全球性的健康问题，由于耐药菌株的出现和BCG疫苗未能提供保护，这种情况进一​​步恶化。迫切需要开发高度灵敏，特异的诊断工具，新颖的疗法和用于根除结核病的疫苗。在本研究中，进行了药理活性化合物库的化学筛选，以鉴定抗分枝杆菌化合物。表型筛选确定了一些新型的小分子抑制剂，包括已知的CDK-2抑制剂NU-6027。我们证明NU-6027在体外抑制牛分枝杆菌BCG的生长，并且还显示与结核分枝杆菌蛋白激酶D（PknD）和蛋白激酶G（PknG）的交叉反应性。比较的结构和序列分析以及对接模拟表明，PknG和PknD的独特结合位点立体化学比其他结核分枝杆菌Ser / Thr蛋白激酶更有利地容纳NU-6027。此外，我们还显示NU-6027处理可诱导巨噬细胞中促凋亡基因的表达。最后，我们证明NU-6027抑制巨噬细胞和小鼠组织中的结核分枝杆菌生长。综上所述，这些结果表明NU-6027可以进

  DOI：

  10.1128/aac.00996-19
• 作为产物：
  描述：

  2,4-二氨基-6-氯嘧啶 、 环己甲醇 在 sodium 作用下， 反应 9.0h， 以46%的产率得到NU6034
  参考文献：
  名称：

  NU-6027通过靶向蛋白激酶D和蛋白激酶G抑制结核分枝杆菌的生长。

  摘要：

  结核病（TB）是一个全球性的健康问题，由于耐药菌株的出现和BCG疫苗未能提供保护，这种情况进一​​步恶化。迫切需要开发高度灵敏，特异的诊断工具，新颖的疗法和用于根除结核病的疫苗。在本研究中，进行了药理活性化合物库的化学筛选，以鉴定抗分枝杆菌化合物。表型筛选确定了一些新型的小分子抑制剂，包括已知的CDK-2抑制剂NU-6027。我们证明NU-6027在体外抑制牛分枝杆菌BCG的生长，并且还显示与结核分枝杆菌蛋白激酶D（PknD）和蛋白激酶G（PknG）的交叉反应性。比较的结构和序列分析以及对接模拟表明，PknG和PknD的独特结合位点立体化学比其他结核分枝杆菌Ser / Thr蛋白激酶更有利地容纳NU-6027。此外，我们还显示NU-6027处理可诱导巨噬细胞中促凋亡基因的表达。最后，我们证明NU-6027抑制巨噬细胞和小鼠组织中的结核分枝杆菌生长。综上所述，这些结果表明NU-6027可以进

  DOI：

  10.1128/aac.00996-19

文献信息

• Cyclin dependent kinase inhibitors
  申请人：Cancer Research Campaign Technology Limited

  公开号：US06677345B1

  公开（公告）日：2004-01-13

  A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHRx where Rx is H or C1-4 alkyl; D is H or NZ1Z2 where Z1 and Z2 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C1-4 alkyl, C1-4 alkoxy, hydroxy, CH2(CH2)nOH (n=1-4), and NRa1Ra2 where Ra1 and Ra2 are each independently H or C1-4 alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D′ is H or NZ3Z4 where Z3 and Z4 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO2, N═N—Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NRe1Re2 or Nre1Nre2Re3 (Re1, Re2 and Re3 each being independently H, C1-4 alkyl, C1-4 hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(Re)═U (Re being hydrogen, C1-4 alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nre′, NORe′ and N—NRe′Re″ where Re′ and Re″ are each independently H, C1-4 alkyl or CONH2), T, CH2T, CHT2 and CT3, where T is a halide I, Br, Cl or F.

  本发明公开了一系列嘧啶衍生物(I)，可以作为细胞周期依赖性激酶（CDK's）的抑制剂，并因此可以提供用于治疗肿瘤或其他细胞增殖障碍的有用治疗化合物。本发明的化合物以一种似乎与已知的CDK抑制剂（如olomoucine和roscovitine）不同的方式结合到CDK分子上。在式(I)中，X是O、S或CHRx，其中Rx是H或C1-4烷基；D是H或NZ1Z2，其中Z1和Z2分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基；A从H、C1-4烷基、C1-4烷氧基、羟基、CH2(CH2)nOH（n=1-4）和NRa1Ra2中选择，其中Ra1和Ra2分别独立地是H或C1-4烷基；Y是或包括一个可选取代的4-至8-成员碳环或杂环；D′是H或NZ3Z4，其中Z3和Z4分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基；E从NO、NO2、N═Ar（其中Ar是可选取代的芳基或可选取代的芳基烷基）、NRe1Re2或Nre1Nre2Re3（Re1、Re2和Re3分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基）、C(Re)═U（Re为氢、C1-4烷基或取代烷基，例如羟基烷基，或未取代或取代的芳基或芳基烷基，例如苄基，U从O、Nre′、NORe′和N—NRe′Re″中选择，其中Re′和Re″分别独立地是H、C1-4烷基或CONH2）、T、CH2T、CHT2和CT3中选择，其中T是卤素I、Br、Cl或F。
• Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors
  作者：Francesco Marchetti、Céline Cano、Nicola J. Curtin、Bernard T. Golding、Roger J. Griffin、Karen Haggerty、David R. Newell、Rachel J. Parsons、Sara L. Payne、Lan Z. Wang、Ian R. Hardcastle

  DOI：10.1039/b925481a

  日期：——

  CDK2 inhibitory structure–activity relationships have been explored for a range of 5-substituted O4-alkylpyrimidines. Variation of the 5-substituent in the 2,6-diaminopyrimidine series confirmed the 5-nitroso substituent as optimal, and showed that 5-formyl and 5-acetyl substituents were also tolerated at this position. A series of O4-alkyl-N2-aryl-5-substituted-6-aminopyrimidines revealed interesting structure–activity relationships. In the 5-nitroso series, the optimum O4-alkyl substituents were cyclohexylmethyl or sec-butyl, combined with a 2-sulfanilyl group. By contrast, in the N2-arylsulfonamido-5-formyl series, the cyclohexylmethyl compound showed relatively poor activity compared with the sec-butyl derivative (22j, (R)-4-(4-amino-6-sec-butoxy-5-formylpyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC50 = 0.8 nM). Similarly, in the N2-arylsulfonamido-5-(hydroxyiminomethyl) series the O4-sec-butyl substituent conferred greater potency than the cyclohexylmethyl (23c, (rac)-4-(4-amino-6-sec-butoxy-5-(hydroxyiminomethyl)pyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC50 = 7.4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g.22j, GI50 = 0.57 μM).

  我们对一系列 5-取代的 O4-烷基嘧啶的 CDK2 抑制结构-活性关系进行了探索。在 2,6-二氨基嘧啶系列中，5-取代基的变化证实了 5-亚硝基取代基是最佳的，并表明 5-甲酰基和 5-乙酰基取代基在该位置上也是可以容忍的。一系列 O4-烷基-N2-芳基-5-取代的 6-氨基嘧啶揭示了有趣的结构-活性关系。在 5-亚硝基系列中，最佳的 O4-烷基取代基是环己基甲基或仲丁基，再加上一个 2-甲磺酰基。相比之下，在 N2-芳基磺酰胺-5-甲酰基系列中，环己基甲基化合物的活性相对低于仲丁基衍生物（22j，(R)-4-(4-氨基-6-仲丁氧基-5-醛基嘧啶-2-基氨基)苯磺酰胺；CDK2 IC50 = 0.8 nM）。同样，在 N2-芳基磺酰胺-5-（羟基亚氨基甲基）系列中，O4-仲丁基取代基比环己基甲基取代基具有更强的效力（23c，(rac)-4-(4-氨基-6-仲丁氧基-5-(羟基亚氨基甲基)嘧啶-2-基氨基)苯磺酰胺；CDK2 IC50 = 7.4 nM）。5- 甲酰基衍生物对 CDK2 的选择性高于 CDK 家族的其他成员，对肿瘤细胞具有生长抑制作用（例如 22j，GI50 = 0.57 μM）。
• 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2
  作者：Veronique Mesguiche、Rachel J Parsons、Christine E Arris、Johanne Bentley、F.Thomas Boyle、Nicola J Curtin、Thomas G Davies、Jane A Endicott、Ashleigh E Gibson、Bernard T Golding、Roger J Griffin、Philip Jewsbury、Louise N Johnson、David R Newell、Martin E.M Noble、Lan Z Wang、Ian R Hardcastle

  DOI：10.1016/s0960-894x(02)00884-3

  日期：2003.1

  The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Identification of Novel Purine and Pyrimidine Cyclin-Dependent Kinase Inhibitors with Distinct Molecular Interactions and Tumor Cell Growth Inhibition Profiles
  作者：Christine E. Arris、F. Thomas Boyle、A. Hilary Calvert、Nicola J. Curtin、Jane A. Endicott、Elspeth F. Garman、Ashleigh E. Gibson、Bernard T. Golding、Sharon Grant、Roger J. Griffin、Philip Jewsbury、Louise N. Johnson、Alison M. Lawrie、David R. Newell、Martin E. M. Noble、Edward A. Sausville、Robert Schultz、Wyatt Yu

  DOI：10.1021/jm990628o

  日期：2000.7.1

  Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O-6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/-: 1 mu M; CDK2, 12 +/- 3 mu M) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, K-i values: CDK1, 2.5 +/- 0.4 mu M; CDK2, 1.3 +/- 0.2 mu M). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI(50) values of 13 +/- 7 mu M and 10 +/- 6 mu M, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.
• CYCLIN DEPENDENT KINASE INHIBITORS
  申请人：Cancer Research Technology Limited

  公开号：EP1066266B1

  公开（公告）日：2005-11-09