NU6021

• 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: NU6021
• 英文别名: 6-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-9H-purin-2-ylamine；6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-7H-purin-2-amine
• 化学式: C₁₁H₁₅N₅O₃
• 分子量: 265.272
• InChiKey: RLXYBYJPRBYHSL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  NU6021 在 溶剂黄146 作用下， 反应 408.0h， 以87%的产率得到NU2040
  参考文献：
  名称：

  Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with O⁶-Substituted Guanine Derivatives

  摘要：

  O-6-Substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B I and CDK2/cyclin A, the O-6 substituent occupying the kinase ribose binding site. Fifty-eight O-6-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic 06 substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O-6-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

  DOI：

  10.1021/jm020056z
• 作为产物：
  描述：

  2-氨基-6-氯嘌呤 、 丙酮缩甘油 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以98%的产率得到NU6021
  参考文献：
  名称：

  Resistance-Modifying Agents. 8. Inhibition of O⁶-Alkylguanine-DNA Alkyltransferase by O⁶-Alkenyl-, O⁶-Cycloalkenyl-, and O⁶-(2-Oxoalkyl)guanines and Potentiation of Temozolomide Cytotoxicity in Vitro by O⁶-(1-Cyclopentenylmethyl)guanine

  摘要：

  A series of O-6-allyl- and O-6-(2-oxoalkyl)guanines were synthesized and evaluated, in comp ari son with the corresponding O-6-alkylguanines, as potential inhibitors of the DNA-repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Simple O-6-alkyl- and O-6-cycloalkylguanines were weak AGT inactivators compared with O-6-allylguanine (IC50 = 8.5 +/- 0.6 muM) With IC50 values ranging from 100 to 1000 muM. The introduction of substituents at C-2 of the allyl group of O-6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O-6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 muM) O-6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 +/- 0.02 muM) and 1-cyclopentenylmethylguanine (IC50 = 0.39 +/- 0.04 muM) exhibiting potency approaching that of the benchmark AGT inhibitor O-6-benzylguanine (IC50 = 0.18 +/- 0.02 muM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 +/- 0.07 muM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O-6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O-6-substituent of each compound makes similar binding interactions within the active site of AGT.

  DOI：

  10.1021/jm000961o

文献信息

• CYCLIN DEPENDENT KINASE INHIBITING PURINE DERIVATIVES
  申请人：CANCERRESEARCHCAMPAIGN TECHNOLOGY LIMITED

  公开号：EP1017394A1

  公开（公告）日：2000-07-12
• [EN] CYCLIN DEPENDENT KINASE INHIBITING PURINE DERIVATIVES<br/>[FR] DERIVES DE PURINE INHIBANT LA KINASE DEPENDANT DE LA CYCLINE
  申请人：——

  公开号：WO1999002162A1

  公开（公告）日：1999-01-21

  [EN] A range is disclosed of purine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDKs) and which thereby c an 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 be different to that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), in preferred embodiments: X is O, S or CHRx where Rx is H or C1-4 alkyl; D is H, halo or NZ1Z2 where Z1 and Z2 are each independently H or C1-4 alkyl or C1-4 hydroxyalkyl; 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; B is selected from H, C1-4 alkyl, C1-4 alkoxy, CF3, an optionally substituted aryl (e.g. phenyl) or an optionally substituted aralkyl (e.g. benzyl), and an hydroxy group that provides a C=O tautomer; and Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; or comprises an optionally substituted linear or branched hydrocarbon chain.
  [FR] L'invention porte sur une gamme de dérivés de purine (I) pouvant agir comme inhibiteurs des kinases dépendant de la cycline (CDK) et pouvant, par conséquent, produire des composés thérapeutiques destinés à être utilisés dans le traitement de tumeurs ou autres troubles de la prolifération cellulaire. Ces composés se lient à des molécules de CDK de façon à être différents de ceux produits par des inhibiteurs connus de CDK tels que olomoucine et roscovitine. Dans la formule (I), selon des réalisations préférées, X représente O, S ou CHRx, Rx représentant H ou alkyle C1-4; D représente H, halo ou NZ1Z2, Z1 et Z2 représentant chacun, indépendamment H, ou alkyle C1-4 ou hydroxyalkyle C1-4; A est sélectionné parmi H, alkyle C1-4, alcoxy C1-4, hydroxy, Ch2(CH2)nOH (n=1-4), et NRa1Ra2, Ra1 et Ra2 représentant chacun, indépendamment, H ou alkyle C1-4; B est sélectionné parmi H, alkyle C1-4, alcoxy C1-4, CF3, un aryle éventuellement substitué (tel que phényle) ou un aralkyle éventuellement substitué (tel que benzyle), et un groupe hydroxy qui produit un tautomère C=O; et Y représente ou comprend un noyau carbocyclique ou hétérocyclique à 4 ou 8 éléments; ou une chaîne d'hydrocarbure linéaire ou ramifiée, éventuellement substituée.
• Resistance-Modifying Agents. 8. Inhibition of <i>O</i>⁶-Alkylguanine-DNA Alkyltransferase by <i>O</i>⁶-Alkenyl-, <i>O</i>⁶-Cycloalkenyl-, and <i>O</i>⁶-(2-Oxoalkyl)guanines and Potentiation of Temozolomide Cytotoxicity in Vitro by <i>O</i>⁶-(1-Cyclopentenylmethyl)guanine
  作者：Roger J. Griffin、Christine E. Arris、Christine Bleasdale、F. Thomas Boyle、A. Hilary Calvert、Nicola J. Curtin、Christine Dalby、Sreenivas Kanugula、Nicola K. Lembicz、David R. Newell、Anthony E. Pegg、Bernard T. Golding

  DOI：10.1021/jm000961o

  日期：2000.11.1

  A series of O-6-allyl- and O-6-(2-oxoalkyl)guanines were synthesized and evaluated, in comp ari son with the corresponding O-6-alkylguanines, as potential inhibitors of the DNA-repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Simple O-6-alkyl- and O-6-cycloalkylguanines were weak AGT inactivators compared with O-6-allylguanine (IC50 = 8.5 +/- 0.6 muM) With IC50 values ranging from 100 to 1000 muM. The introduction of substituents at C-2 of the allyl group of O-6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O-6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 muM) O-6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 +/- 0.02 muM) and 1-cyclopentenylmethylguanine (IC50 = 0.39 +/- 0.04 muM) exhibiting potency approaching that of the benchmark AGT inhibitor O-6-benzylguanine (IC50 = 0.18 +/- 0.02 muM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 +/- 0.07 muM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O-6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O-6-substituent of each compound makes similar binding interactions within the active site of AGT.
• Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with <i>O</i>⁶-Substituted Guanine Derivatives
  作者：Ashleigh E. Gibson、Christine E. Arris、Johanne Bentley、F. Thomas Boyle、Nicola J. Curtin、Thomas G. Davies、Jane A. Endicott、Bernard T. Golding、Sharon Grant、Roger J. Griffin、Philip Jewsbury、Louise N. Johnson、Veronique Mesguiche、David R. Newell、Martin E. M. Noble、Julie A. Tucker、Hayley J. Whitfield

  DOI：10.1021/jm020056z

  日期：2002.8.1

  O-6-Substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B I and CDK2/cyclin A, the O-6 substituent occupying the kinase ribose binding site. Fifty-eight O-6-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic 06 substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O-6-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.