6-O-Benzylguanine
[CAS# 19916-73-5]

Identification

• Classification: API >> Inhibitor drug
• Name: 6-O-Benzylguanine
• Synonyms: 2-Amino-6-(benzyloxy)purine; 2-Amino-6-(phenylmethoxy)-9H-purine
• Molecular Formula: C₁₂H₁₁N₅O
• Molecular Weight: 241.25
• CAS Registry Number: 19916-73-5
• EC Number: 633-744-5
• SMILES: C1=CC=C(C=C1)COC2=NC(=NC3=C2NC=N3)N

Properties

• Density: 1.4±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.743, Calc.^*
• Boiling Point: 621.4±63.0 °C (760 mmHg), Calc.^*
• Flash Point: 329.6±33.7 °C, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

6-O-Benzylguanine is a synthetic guanine derivative that has been widely studied for its role in overcoming resistance to alkylating agents in cancer therapy. This compound functions as an inhibitor of the O6-methylguanine-DNA methyltransferase (MGMT) enzyme, which is responsible for repairing alkylated DNA and thereby reducing the effectiveness of certain chemotherapeutic agents. By inhibiting MGMT, 6-O-Benzylguanine enhances the cytotoxic effects of alkylating drugs, making it a promising candidate for combination cancer treatments.

The discovery of 6-O-Benzylguanine was driven by the need to counteract MGMT-mediated resistance to alkylating chemotherapies such as temozolomide and carmustine. Researchers synthesized this compound through selective benzylation of guanine at the O6 position, followed by purification and structural confirmation using nuclear magnetic resonance (NMR) and mass spectrometry (MS). Initial studies demonstrated that 6-O-Benzylguanine effectively binds to MGMT, leading to irreversible inactivation of the enzyme. This mechanism allows alkylating agents to exert their full cytotoxic potential on cancer cells, particularly in glioblastomas and other MGMT-expressing tumors.

The primary application of 6-O-Benzylguanine lies in its role as an MGMT inhibitor in cancer therapy. When administered alongside alkylating agents, it prevents MGMT from repairing DNA lesions caused by chemotherapy, thereby increasing the susceptibility of tumor cells to treatment. Preclinical and clinical studies have shown that this combination approach enhances the efficacy of alkylating drugs, leading to improved treatment outcomes in glioblastoma and other difficult-to-treat cancers. However, one of the challenges associated with 6-O-Benzylguanine is its potential to increase toxicity in normal cells, necessitating careful dosing strategies to maximize therapeutic benefit while minimizing side effects.

Beyond its application in oncology, 6-O-Benzylguanine has also been explored in gene therapy research. Since MGMT confers resistance to alkylating agents, researchers have investigated the use of MGMT gene modifications in hematopoietic stem cells to protect normal bone marrow during chemotherapy. In this context, 6-O-Benzylguanine serves as a tool to selectively target non-modified cells, allowing for the preferential survival of genetically modified, chemotherapy-resistant stem cells. This approach has potential implications for improving the safety and effectiveness of high-dose chemotherapy regimens.

In addition to its medical applications, 6-O-Benzylguanine has been employed as a biochemical probe in molecular biology studies. Researchers have used it to investigate the function and regulation of MGMT, as well as to explore the broader implications of DNA repair mechanisms in cancer biology. Its ability to selectively inhibit MGMT has made it a valuable tool for studying the role of DNA damage and repair in tumor progression and therapeutic resistance.

Despite its potential, the clinical use of 6-O-Benzylguanine remains limited due to challenges in optimizing its pharmacokinetics and reducing systemic toxicity. Researchers continue to explore structural modifications and alternative MGMT inhibitors that retain the beneficial effects of 6-O-Benzylguanine while minimizing its drawbacks. Advances in targeted drug delivery and combination therapy strategies may further enhance its clinical viability in the future.

In summary, 6-O-Benzylguanine is a critical compound in the field of cancer therapy, particularly for overcoming resistance to alkylating agents. Its discovery has provided valuable insights into DNA repair mechanisms and has led to innovative approaches in oncology and gene therapy. Ongoing research aims to refine its applications, ensuring its continued impact on cancer treatment strategies.

References

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DOI: 10.1186/s12645-023-00242-2

2024. Enhancing Temozolomide (TMZ) chemosensitivity using CRISPR-dCas9-mediated downregulation of O6-methylguanine DNA methyltransferase (MGMT). *Journal of Neuro-Oncology*.
DOI: 10.1007/s11060-024-04708-0

2023. Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells. *Biochemical and Biophysical Research Communications*.
DOI: 10.1016/j.bbrc.2023.08.050

2023. TTD: Therapeutic Target Database describing target druggability information. *Nucleic Acids Research*.
DOI: 10.1093/nar/gkad751

2023. Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules. *Nature Chemical Biology*.
DOI: 10.1038/s41589-023-01464-6