Investigating the Stability of Six Phenolic TMZ Ester Analogues, Incubated in the Presence of Porcine Liver Esterase and Monitored by HPLC

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-05, Vol.27 (9), p.2958
• Main Authors: Shervington, Leroy A, Ingham, Oliver
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Alkylating - pharmacology; Brain Neoplasms - drug therapy; Brain tumors; Cell Line, Tumor; Chromatography, High Pressure Liquid; Deoxyribonucleic acid; DNA; DNA Modification Methylases; DNA Repair Enzymes - genetics; Drug development; Drug Resistance, Neoplasm; Enzymes; Esterase; Esterases; Esters; Esters - pharmacology; Glioblastoma; Glioblastoma - drug therapy; glioblastoma multiform (GBM); High performance liquid chromatography; Hydrogen bonds; Hydrolysis; Liquid chromatography; Liver; Liver - metabolism; Metabolism; Methylguanine; Phenolic compounds; phenolic TMZ esters; Phenols; porcine liver esterase (PLE); Radiation therapy; Stability; Swine; Temozolomide; temozolomide (TMZ); Temozolomide - pharmacology; Tumor Suppressor Proteins - metabolism
• ISSN: 1420-3049; 1420-3049
• 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.