Synthesis and Characterization of a Series of Temozolomide Esters and Its Anti-glioma Study
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Published on: March 28, 2021
Yawen Yu1, Liangxiao Wang1, Junping Han1
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
Abstract:
Temozolomide is a first-line therapeutic drug for glioblastoma (GBM), and it has a low solubility, short biological half-life, and resistance to drug limits in clinical applications. Therefore, it is necessary to find more effective anti-tumor drugs to overcome drug resistance and enhance its anti-glioma activity. We therefore used n-butanol, n-hexanol, n-octanol, 1-dodecanol and 1-hexadecanol to synthesize a series of temozolomide ester compounds (TMZEs) and then investigated their physicochemical properties and anti-glioma efficacy. Our results showed that TMZEs had a higher lipophilicity compared to TMZ and could stably exist in plasma and brain homogenates. TMZEs had significantly increased cytotoxicity and cellular uptake in C6 glioma cells as chain lengths increased. Additionally, the IC50 of TMZ-16E towards TMZ-resistant cells (T98G) was 85.9-fold lower than that of TMZ (p < 0.001), and Western blot results demonstrated that TMZ-16E could significantly reduce the expression of O6-methylguanine-DNA-methyltransferase (MGMT). The in vivo anti-glioma efficacy of TMZ-16E were then investigated in orthotopic and subcutaneous GBM models. TMZ-16E prolonged the survival time to 35 days in orthotopic glioma bearing rats, which was 1.94-fold longer than the survival time of rats treated with TMZ, and TMZ-16E increased tumor cell apoptosis based on TUNEL staining. Moreover, TMZ-16E (50 mg/kg) noticeably slowed the growth of T98G subcutaneous tumors by down-modulating MGMT expression in subcutaneous GBM-bearing mice, indicating that TMZ-16E could effectively reverse drug resistance. In conclusion, TMZEs improved the lipophilicity and stability of these drugs. Especially, TMZ-16E could reverse drug resistance and improve therapeutic effects of TMZ, which has clinical application potential for GBM treatment.
Insights
New temozolomide ester compounds (TMZEs) show enhanced lipophilicity and stability, effectively overcoming drug resistance in glioblastoma (GBM) models. The compound TMZ-16E significantly improved anti-glioma activity and reversed resistance, showing clinical potential for GBM treatment.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Temozolomide (TMZ) is a first-line glioblastoma (GBM) treatment but faces limitations due to low solubility and drug resistance.
- Developing novel analogs is crucial to enhance anti-glioma efficacy and overcome resistance mechanisms.
Purpose of the Study:
- To synthesize and evaluate novel temozolomide ester compounds (TMZEs) with improved physicochemical properties and anti-glioma activity.
- To investigate the potential of TMZEs in overcoming TMZ resistance in glioblastoma models.
Main Methods:
- Synthesis of a series of TMZEs using various long-chain alcohols.
- Assessment of physicochemical properties, including lipophilicity and stability in plasma and brain homogenates.
- In vitro evaluation of cytotoxicity and cellular uptake in C6 and T98G (TMZ-resistant) glioma cells.
- In vivo efficacy studies in orthotopic and subcutaneous GBM rat and mouse models.
- Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) expression via Western blot and apoptosis via TUNEL staining.
Main Results:
- TMZEs exhibited increased lipophilicity and stability compared to TMZ.
- TMZEs demonstrated enhanced cytotoxicity and cellular uptake in glioma cells, with efficacy increasing with chain length.
- TMZ-16E showed significantly lower IC50 values in TMZ-resistant T98G cells and reduced MGMT expression.
- In vivo studies confirmed TMZ-16E's ability to prolong survival in orthotopic GBM models and inhibit tumor growth in subcutaneous models by down-modulating MGMT.
Conclusions:
- TMZEs possess improved lipophilicity and stability, offering advantages over conventional TMZ.
- TMZ-16E effectively reverses drug resistance in glioblastoma by targeting MGMT.
- TMZ-16E demonstrates significant therapeutic potential for clinical application in GBM treatment.
