The Synthesis and Biological Assessment of Novel Ursolic Acid Derivatives as Potential Chemotherapeutic Agents for Cancer
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1.6 BIOLOGICAL SCIENCES, 3. MEDICAL AND HEALTH SCIENCES, Health care sciences and services, Public and environmental health
Glioblastoma (GBM) is considered to be the most biologically aggressive type of brain tumour accounting for approximately 48% of all malignant primary brain tumours. GBM patients diagnosed have poor prognosis with a low five-year survival rate of
The aim of this study was to develop novel UA derivatives to enhance its bioavailability. Nine novel UA derivatives: three different diamine linkers, with Boc-protected and deprotected ends, and with folic acid were designed and synthesized to improve compound activity and/or delivery. The structures of the newly synthesised compounds were confirmed using mass spectrometry, FTIR, 1H NMR and 13C NMR. The structural activity relationship (SAR) of UA and novel UA derivatives that were designed to improve its activity and bioavailability (predicted ADMET profile) were explored, and molecular docking studies against proposed targets – FOLR1 and/or VRK1 were utilised, with an in-depth analysis of predicted interactions. The cytotoxic activity was determined using alamarBlueTM cell viability assay in a panel of cancer cell lines and normal cells. It was found that the conjugation of folic acid to UA decreased its cytotoxic activity. Interestingly, our study showed that the Boc-protected compounds have delayed cytotoxicity in comparison to deprotected compounds, which are more evident in U-251 MG and A431 cell lines using 2D cell culture assay. Whereas in 3D cell culture, only deprotected compounds exhibited an activity. The deprotected novel UA derivatives also retained the inherent anti-proliferative and anti-migratory effect of UA in U-251 MG cells. The synergistic studies focusing on the cell membrane damage performed showed that novel UA derivatives (7 – 12) may have a protective effect when exposed to radioactivity. In addition, the initial inhibitor studies suggests that compounds 8 and 10 at longer timepoint, may trigger multiple cell demise pathway. Based on these preliminary results, this study provides a new insight into using novel UA derivatives and a possible MOA for their anti-cancer effect.
Mondala, J. R. M. (2022). The Synthesis and Biological Assessment of Novel Ursolic Acid Derivatives as Potential Chemotherapeutic Agents for Cancer. Technological University Dublin. DOI: 10.21427/RG1V-6C66
Technological University Dublin
Thesis submitted to the School of Food Science and Environmental Health, Technological University Dublin, in fulfilment of the requirements for PhD examination, November 2022.