Phytochemical, anti-cancer, anti-inflammatory and neuroprotective studies on compounds isolated from Malaysian plants, Aquilaria malaccensis and Hopea dryobalanoides

  • S Siti Aisya Binti Saud Gany

Student thesis: Doctoral Thesis

Abstract

Natural products have been used for medicinal purposes for centuries and remain the main source of new drugs to treat diseases due to their biological activities such as anticancer, anti-inflammatory and neuroprotective effects. This thesis aimed to : 1) isolate bioactive compounds from two Malaysian plants which are: Aquilaria malaccensis and Hopea dryobalanoides using column chromatography and characterised them by nuclear magnetic resonance (NMR); 2) assess the anti-cancer activity of the isolated compounds through various in vitro assays and metabolomics profiling; 3) investigate the anti-inflammatory properties of the compounds by inhibition of the pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6)) levels in response to lipopolysaccharide (LPS) stimulation in macrophage cells and identify the effects of the compound treatments on the gene expression against the inflammatory response caused by LPS-stimulated macrophage cells; 4) examine the protective effects of the compounds against oxidative stress induced in neuron cells.1) Plants extracts, investigated phytochemically, resulted in the isolation of 7-methoxyacacetin (7-aca) from the hexane extract of A. malaccensis twigs for the first time, a mixture of two compounds quercitrin and afzelin (Q/A) from the methanol extract of A. malaccensis twigs and two compounds named balanocarpol (bala) and heimiol A from the ethyl acetate extract of H. dryobalanoides bark. There are limited reports on the biological activity of 7-aca, however a similar compound called acacetin (aca) has been reported to have a range of bioactivates including anti-cancer, anti-inflammatory and protective effects. Therefore, aca was purchased commercially for comparison purposes.;2) Cytotoxicity screening of 7-aca, aca, Q/A and bala resulted in decreased viability of A2780 (ovarian) and ZR-75-1 (breast) cells in a concentration dependant manner. 7-Aca exhibited a more potent cytotoxicity against A2780 and ZR-75-1 cells (IC50=7.9µM and 8.5µM, respectively) compared to aca (IC50= 19.5µM and 17.5µM,respectively). Heimiol A did not show toxic effects against both cancer cells even at the highest concentration (150µM). All compounds showed selective toxicity toward the cancers cells, as they did not cause toxicity against normal PNT2A (prostate) cells. Further investigation behind the cytotoxic effect of the compounds revealed that 7-aca,aca, Q/A and bala caused the production of ROS, depletion of mitochondria membrane potential (ΔΨM) and an increase in caspase-3/7 levels in A2780 and ZR-75-1 cells. Many studies have reported that an excessive increase in ROS in cancer cells disrupts the mitochondrial membrane thus causing the loss of ΔΨM that leads to activation of effectors such as caspase-3, which eventually result in apoptotic cell death. Moreover,7-aca showed the strongest anti-metastatic effects through the inhibition of adhesion of cancer cells to the ECM protein fibronectin as well as inhibiting the migration and invasion of A2780 and ZR-75-1 cells by approximately 50-70%. The overall results revealed that 7-aca showed a stronger anti-cancer effects towards both cancer cells compared to aca and bala. Due to the more potent activity shown by 7-aca, A2780 and ZR-75-1 cells treated with 7-aca was chosen for metabolite analysis of cell lysates and aca was used as comparison. Several biomarker metabolites were decreased significantly (P
Date of Award4 Mar 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SupervisorValerie Ferro (Supervisor) & Louise Young (Supervisor)

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