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.

替莫唑胺是胶质母细胞瘤（GBM）的一线治疗药物，在临床应用中具有溶解度低、生物半衰期短、抗药限的特点。因此，有必要寻找更有效的抗肿瘤药物来克服耐药性，增强其抗胶质瘤活性。因此，我们使用正丁醇、正己醇、正辛醇、1-十二醇和 1-十六醇合成了一系列替莫唑胺酯化合物 (TMZE)，然后研究了它们的理化性质和抗胶质瘤功效。我们的结果表明，与 TMZ 相比，TMZE 具有更高的亲脂性，并且可以稳定存在于血浆和脑匀浆中。随着链长度的增加，TMZEs 在 C6 神经胶质瘤细胞中的细胞毒性和细胞摄取显着增加。此外，IC ₅₀TMZ-16E对TMZ抗性细胞（T98G）的抑制作用比TMZ低85.9倍（p  < 0.001），Western blot结果表明TMZ-16E可显着降低O ^{6 -}甲基鸟嘌呤-DNA-甲基转移酶的表达( MGMT )。的体内TMZ-16E的抗神经胶质瘤功效然后在原位和皮下GBM模型研究。TMZ-16E 将原位胶质瘤大鼠的存活时间延长至 35 天，比 TMZ 治疗的大鼠的存活时间长 1.94 倍，并且基于 TUNEL 染色，TMZ-16E 增加了肿瘤细胞凋亡。此外，TMZ-16E (50 mg/kg) 通过下调MGMT显着减缓了 T98G 皮下肿瘤的生长在皮下携带 GBM 的小鼠中表达，表明 TMZ-16E 可以有效逆转耐药性。总之，TMZE 提高了这些药物的亲脂性和稳定性。尤其是TMZ-16E能够逆转耐药性，提高TMZ的治疗效果，在GBM治疗中具有临床应用潜力。