School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
Kindeva Drug Delivery, Bakewell Road, Loughborough LE11 5RB, UK.
Molecules. 2022 May 5;27(9):2958. doi: 10.3390/molecules27092958.
Previous published data from our group showed the encouraging in vitro activities of six phenolic temozolomide (TMZ) ester analogues (ES8-ES12 and ES14) with up to a five-fold increase in potency compared to TMZ against glioblastoma multiform cell lines and TMZ-resistant O-methylguanine-DNA methyl transferase (MGMT)-positive primary cells. This study investigated the stabilities of the six phenolic TMZ ester analogues in the presence of porcine liver esterase (PLE) as a hydrolytic enzyme, using high-performance liquid chromatography (HPLC), monitored by a diode-array detector (DAD). Determining the rates of hydrolysis of the esters provided a useful insight into the feasibility of progressing them to the next phase of drug development. Fifty percent of TMZ esters consisting of nitro, chloro, phenyl and tolyl groups (ES9, ES10, ES12 and ES14) were hydrolysed within the first 4.2 min of PLE exposure, while the TMZ esters consisting of methoxy and nitrile groups (ES8 and ES11) demonstrated increased stability, with 50% hydrolysis achieved in 7.3 and 13.7 min, respectively. In conclusion, the survival of these phenolic TMZ esters on route to the target site of a brain tumor would be a challenge, mainly due to the undesirable rapid rate of hydrolysis. These findings therefore pose a question regarding the effectiveness of these esters in an in vivo setting.
先前我们小组发表的数据显示，六种酚类替莫唑胺（TMZ）酯类似物（ES8-ES12 和 ES14）具有令人鼓舞的体外活性，与 TMZ 相比，对多形性胶质母细胞瘤细胞系和 TMZ 耐药的 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）阳性原代细胞的活性增加了五倍。本研究使用高效液相色谱法（HPLC），通过二极管阵列检测器（DAD）监测，研究了六种酚类 TMZ 酯类似物在猪肝酯酶（PLE）存在下的稳定性，PLE 是一种水解酶。酯的水解速率的测定为它们能否进入药物开发的下一阶段提供了有用的见解。含有硝基、氯、苯基和甲苯基的 TMZ 酯（ES9、ES10、ES12 和 ES14）在 PLE 暴露的最初 4.2 分钟内有 50%被水解，而含有甲氧基和腈基的 TMZ 酯（ES8 和 ES11）则表现出更高的稳定性，分别需要 7.3 和 13.7 分钟才能达到 50%水解。总之，这些酚类 TMZ 酯在到达脑肿瘤靶部位的过程中存活下来将是一个挑战，主要是由于水解的速度过快。因此，这些发现对这些酯类在体内环境中的有效性提出了质疑。
