Abstract:
Trioxatriangulenium 1 (TOTA⁺) is a planar carbocation that exhibits DNA intercalating properties. Interestingly, this class of compounds could potentially be used to target cancer cells, because of their pH switchable properties, which allows them to change their shape from a planar (acidic pH, bioactive) to a non-planar (basic pH, bio-inactive) structure. Cancer cell environments have been shown to be more acidic that non-cancerous, which allows the change to the bioactive form. A preliminary study of the antiproliferative activity of TOTA⁺ against a triple-negative breast cancer cell line (MDA-MB-231) and a colon cancer cell line (HCT-116) was conducted and showed inhibition of cell growth with IC50 of 302 ± 6.52 nM in MDA-MB-231 and 1.2 ± 0.03 μM in HCT-116. After these results a range of analogues of TOTA⁺ 1 were to be synthesized in order to determine a structure activity relationship (SAR) for this class of compounds and improve its potency and selectivity towards cancerous cells. Three different series of TOTA+ derivatives were synthesized. The first series consisted of acyclic compounds, which can be divided into three separate sub-series with increasing planarity; completely non-planar tris(2,6-dimethoxyphenyl)methylium ions ((DMP)3C + ), tetramethoxyphenyl acridinium ions (TMPAs+ ) and dimethoxy quinacridinium ions (DMQAs+ ). The second series consisted of completely cyclic TOTA+ analogues, which can be divided into three separate sub-series; azadioxatriangulenium ions ADOTAs+ , containing one N-bridge, diazaoxatriangulenium ions DAOTAs+ , containing two N-bridges and triazatriangulenium ions TATAs+ , containing three N-bridges. Additional synthesized compounds included linked dimers incorporating TMPA+ , DMQA+ , ADOTA+ and DAOTA+ moieties. In all, a total of 107 compounds were prepared to develop the SAR. The theoretical binding of the synthesized compounds with DNA were analysed using molecular modelling docking studies using Gold software. Additionally, these compounds underwent biological testing at the Auckland Cancer Society Research Centre (ACSRC) to determine their antiproliferative activities. The studies of both in silico method and experimental biological assays allowed the comparison of the two processes, to determine the accuracy of the docking methods to predict the activity. A large number of tested compounds showed noticeably improved inhibitory activity over the lead compound, TOTA+ 1. A total 13 compounds for MDA-MB-231 and 11 compounds for iii HCT-116 cell lines showed IC50 < 200 nM, of which two compounds (41f and 156a) showed greater activity compared to the clinically used drug, Camptothecin. The findings presented in this thesis have developed a SAR of this novel class of DNA-binding agents.