161058-83-9

Basic information

• Product Name: NU 2058
• Synonyms: 6-(Cyclohexylmethoxy)-9H-purin-2-amine;2-aMino-6-purine;2-aMino-6-[(cyclohexylMethyl)oxy]purine;2-Amino-6-(cyclohexylmethoxy)purine
• CAS NO: 161058-83-9
• Molecular Formula: C₁₂H₁₇N₅O
• Molecular Weight: 247.3
• Product Categories: Protein Kinase;Cell Cycle Regulation
• Mol File: 161058-83-9.mol

Chemical Properties

• Melting Point: 199°C(lit.)
• Boiling Point: 580.8°C at 760 mmHg
• Flash Point: 305°C
• Appearance: white/
• Density: 1.299g/cm³
• Vapor Pressure: 1.76E-13mmHg at 25°C
• Refractive Index: 1.649
• Storage Temp.: 2-8°C
• Solubility: DMSO: 22 mg/mL
• PKA: 7.36±0.20(Predicted)
• CAS DataBase Reference: NU 2058(CAS DataBase Reference)
• NIST Chemistry Reference: NU 2058(161058-83-9)
• EPA Substance Registry System: NU 2058(161058-83-9)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36/37
• WGK Germany: 3
• Hazardous Substances Data: 161058-83-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
NU 2058 is used as an inhibitor for cyclin-dependent kinases (Cdk1 and Cdk2) to arrest cell cycling in cancer cells, potentially leading to cell death. This makes it a promising candidate for the development of cancer treatments.
Used in Anticancer Applications:
NU 2058 is used as an anticancer agent due to its ability to induce cell-cycle arrest at the G2-M phase and potentiate the apoptotic effect of pacitaxel, a widely used chemotherapy drug. This selectivity against Cdk2-cyclin A may contribute to its effectiveness in treating various types of cancer.
Used in Drug Development:
As an intermediate of NU 6140 (N925295), a cyclin-dependent kinase 2 inhibitor, NU 2058 plays a role in the development of new drugs targeting Cdk2 for cancer treatment. Its selectivity and potency make it a valuable compound in the search for more effective and targeted cancer therapies.

Biological Activity

Cyclin-dependent kinase (cdk) 1 and cdk2 inhibitor (K i values are 5 and 12 μ M respectively). Inhibits growth of human tumor cells in vitro (mean GI 50 = 13 μ M). Also inhibits DNA topoisomerase II ATPase activity (IC 50 = 300 μ M).

InChI:InChI=1/C12H17N5O/c13-12-16-10-9(14-7-15-10)11(17-12)18-6-8-4-2-1-3-5-8/h7-8H,1-6H2,(H3,13,14,15,16,17)

Upstream product

• 100-49-2 cyclohexylmethyl alcohol 
• 10310-21-1 2-Amino-6-chloropurin 

Downstream Products

• 444723-30-2 6-(cyclohexylmethoxy)-2-fluoro-9H-purine 

Relevant articles and documents

Facilitation of displacements at the 6-position of purines by the use of 1,4-diazabicyclo[2.2.2]octane as leaving group

Reactions of 6-chloropurines with 1,4-diazabicyclo[2.2.2]octane (DABCO) give the corresponding 'DABCO-purines' 1a-d, which undergo facile displacement reactions with alkoxides in dimethyl sulfoxide to afford 6-oxy-substituted purines.

Effect of O6-substituted guanine analogs on O6-methylguanine DNA-methyltransferase Expression and glioblastoma cells viability

Background: Glioblastoma multiforme (GBM) is often associated with a poor survival prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6-methylguanine DNA-methyltransferase (MGMT). Objectives: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to TMZ. Methods: Twenty-five O6-alkyl, O6-aryl and O6-substituted-aryl guanine analogs including nine novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the T98G GBM cells viability. Results: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24 emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog (19), bearing a p-nitrobenzyl moiety, reduced considerably the O6-methylguanine DNA-methyltransferase expression level. When combined with TMZ (1), which is used as first line treatment for brain tumors, compounds 19, 22, and 24 decreased T98G cells?proliferation by 32%, 68% and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further supporting the notion that this cell model is resistant to this alkylating agent. Conclusion: Overall, these results notably highlight a group of MGMT inhibitors that warrants further exploration in the development of therapeutic options to circumvent TMZ resistance in brain tumors.

6-Oxo and 6-thio purine analogs as antimycobacterial agents

6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N 9-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb.

Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6- Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (K(i) values: CDK1, 5 ± 1 μM; CDK2, 12 ± 3 μM) 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 μM; CDK2, 1.3 ± 0.2 μM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 ± 7 μM and 10 ± 6 μM, 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.

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

A series of O6-allyl- and O6-(2-oxoalkyl)guanines were synthesized and evaluated, in comparison with the corresponding O6-alkylguanines; as potential inhibitors of the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Simple O6-alkyl- and O6-cycloalkylguanines were weak AGT inactivators compared with O6-allylguanine (IC50 = 8.5 ± 0.6 μM)with IC50 values ranging from 100 to 1000 μM. The introduction of substituents at C-2 of the allyl group of O6-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O6-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 μM). O6-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC50 = 0.55 ± 0.02 μM) and 1-cyclopentenylmethylguanine(IC50 = 0.39 ± 0.04 μM) exhibiting potency approaching that of the benchmark AGT inhibitor O6-benzylguanine (IC50 = 0.18 ± 0.02 μM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC50 = 0.20 ± 0.07 μM) 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 O6-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O6-substituent of each compound makes similar binding interactions within the active site of AGT.