Tetrahydroquinoline derivatives for the development of anti-glioblastoma agents
Vila Alonso, Anxo (2024)
2024
Master's Programme in Biomedical Sciences and Engineering
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
Hyväksymispäivämäärä
2024-05-13
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202404224062
https://urn.fi/URN:NBN:fi:tuni-202404224062
Tiivistelmä
Glioblastoma multiforme (GBM) is one of the most important brain tumors due to its high mortality and difficult treatment. Several treatments against GBM have been developed including surgery, radiotherapy, and chemotherapy. Chemotherapy is the most effective in improving the life expectancy of the patients. The standard chemotherapeutic agent for GBM is temozolomide (TMZ), which is usually given in combination with radiotherapy and surgery. However, this type of therapy has shown several side effects and developed drug resistance leading to adverse effects. Therefore, developing a novel chemotherapeutic drug against GBM is demanding. Over the last decades, several new compounds have been synthetized and proved to be effective against GBM cell proliferation. Among these agents, phenolic compounds have gained the attention due to their wide variety of anti-therapeutic properties against several cancers, including GBM. Therefore, investigating this family of compounds could possibly lead to explore new and more effective drugs.
Recently, our research group have shown the effective inhibition of GBM cell growth using a novel alkylaminophenol derivative, 2-((3,4-dihydroquinolin-1(2H)-yl)-(p-tolyl) methyl) phenol (THTMP). THTMP was able to induce the apoptosis in different glioblastoma cell lines, making it a good candidate for clinical testing. In this study, to improve the efficacy of the THTMP, it was modified to obtain novel tetrahydroquinoline derivatives with potential new therapeutic effects. We investigated eight novel THTMP derivatives synthesized via the Petasis borono-Mannich process to test their potential cytotoxicity in GBM cells and compared the results to the current standard chemotherapy drug, temozolomide. From the preliminary cytotoxicity analysis, top two compounds D.02 and D.05 were selected for further in-vitro analysis. The half-maximal inhibitory concentrations for GBM cell lines LN229 and SNB19 were 1.82 μM and 7.82 μM for D.02, and 5.14 μM and 9.73 μM for D.05. as 1.82 μM and 7.82 μM for the GBM cell lines LN229 and SNB19, respectively. Time-dependent study validated D.02 as having a better overall cytotoxicity effect as time progressed. Cell growth inhibition showed similar or higher effect for the top leads than the temozolomide. Also, D.02 and D.05 showed nil cytotoxicity effect in non-cancerous cells, mouse embryonic fibroblast (MEF) cell line, revealed its selective inhibition against GBM cells. In addition, the effect of these compounds was tested using a scratch assay revealed its ability to inhibit the invasiveness of the cells than TMZ. Additionally, cell cycle arrest, apoptosis, ROS, and mitochondrial membrane potential analyses were carried out to investigate the mode of action of the top drugs in triggering GBM cell death. Overall, the current thesis provides a comprehensive data on the preclinical investigation of novel tetrahydroquinoline derivatives against GBM cell growth. Further molecular investigation on the effect of these top leads will explore the significant genes and crucial downstream signaling pathways involved in GBM growth inhibition.
Recently, our research group have shown the effective inhibition of GBM cell growth using a novel alkylaminophenol derivative, 2-((3,4-dihydroquinolin-1(2H)-yl)-(p-tolyl) methyl) phenol (THTMP). THTMP was able to induce the apoptosis in different glioblastoma cell lines, making it a good candidate for clinical testing. In this study, to improve the efficacy of the THTMP, it was modified to obtain novel tetrahydroquinoline derivatives with potential new therapeutic effects. We investigated eight novel THTMP derivatives synthesized via the Petasis borono-Mannich process to test their potential cytotoxicity in GBM cells and compared the results to the current standard chemotherapy drug, temozolomide. From the preliminary cytotoxicity analysis, top two compounds D.02 and D.05 were selected for further in-vitro analysis. The half-maximal inhibitory concentrations for GBM cell lines LN229 and SNB19 were 1.82 μM and 7.82 μM for D.02, and 5.14 μM and 9.73 μM for D.05. as 1.82 μM and 7.82 μM for the GBM cell lines LN229 and SNB19, respectively. Time-dependent study validated D.02 as having a better overall cytotoxicity effect as time progressed. Cell growth inhibition showed similar or higher effect for the top leads than the temozolomide. Also, D.02 and D.05 showed nil cytotoxicity effect in non-cancerous cells, mouse embryonic fibroblast (MEF) cell line, revealed its selective inhibition against GBM cells. In addition, the effect of these compounds was tested using a scratch assay revealed its ability to inhibit the invasiveness of the cells than TMZ. Additionally, cell cycle arrest, apoptosis, ROS, and mitochondrial membrane potential analyses were carried out to investigate the mode of action of the top drugs in triggering GBM cell death. Overall, the current thesis provides a comprehensive data on the preclinical investigation of novel tetrahydroquinoline derivatives against GBM cell growth. Further molecular investigation on the effect of these top leads will explore the significant genes and crucial downstream signaling pathways involved in GBM growth inhibition.