Department of Chemistry and Polymer Science

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Browsing Department of Chemistry and Polymer Science by Subject "1,2,3-triazoles"

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    The synthesis, characterization and preliminary biological evaluation of triazole complexes of palladium
    (Stellenbosch : Stellenbosch University, 2017-03) Van Niekerk, Annick; Mapolie, Selwyn Frank; Stellenbosch University. Faculty of Engineering. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Palladium based anti-cancer agents have been identified as potential replacements for known platinum based chemotherapeutics. However, only a limited number of these compounds have managed to progress beyond the laboratory due to a lack of understanding surrounding their mode of action and structure activity relationships. Hence, the aim of this study was to synthesize a small library of trans-Pd(II)-1-substituted-4-phenyl-1,2,3-triazolyl and N,N’-bidentate Pd(II)-1-substituted- 4-pyridyl-1,2,3-triazolyl complexes for evaluation against human breast cancer cell lines. The DNA interaction modes of the active compounds were investigated with DNA migration and DNA titration studies. A number of known (1a – 3a, 7a – 9a, 1b – 3b, 7b, 9b) and novel (4a – 6a, 4b – 6b, 8b) 1-substituted- 4-phenyl-1,2,3-triazole and 1-substituted-4-pyridyl-1,2,3-triazole ligands were synthesized, in moderate to good yields. The N-bound substituents were varied in order to investigate the effects of sterics, electronics and hydrophilicity on the cytotoxicity of the resulting complexes. All ligands were characterized using FTIR, 1H NMR and 13C NMR spectroscopy, as well as ESI-MS spectrometry. Elemental analysis was also employed to confirm the purity of the compounds. Complexation of 1a – 9a to Pd(II) yielded the trans-Pd(II)-phenyl-1,2,3-triazolyl complexes (T1a – T9a) in moderate to good yields. It was observed that these compounds dissociate in DMSO and an NMR study was conducted to confirm that ligand exchange indeed takes place. Complexation of ligands 1b – 9b to Pd(II) yielded the N,N’-bidentate-Pd(II)-pyridyl-1,2,3-triazolyl complexes (N1b – N9b) in moderate to good yields. Unlike the trans-Pd(II)-1-substituted-4-phenyl-1,2,3-triazolyl complexes, the N,N’-bidentate-Pd(II)-pyridyl-1,2,3-triazolyl complexes displayed no signs of ligand exchange in DMSO. Characterization of all complexes was carried out using FTIR, 1H and 13C NMR spectroscopy, ESI-MS and elemental analysis. The kinetic solubility in a 2 % (V/V) DMSO/PBS solution of all complexes was determined using a turbidimetric assay. It was found that all complexes were moderately soluble with the exception of complexes T2a, T7a, T9a and N1b. The cytotoxicity of these complexes were thus evaluated as suspensions. Owing to the ligand dissociation observed for complexes T1a – T9a, the cytotoxicity observed for the treatment of cells with these complexes cannot be ascribed to the activity of the original complexes but rather to a mixture of species in solution. The cytotoxicity of the complexes was evaluated employing a MTT Assay (3-(4,5-dimethylthiazol-2- yl)-2,5-diphenylterazolium bromide assay) against breast adenocarcinoma cell lines MCF-7 and MDA-MB-231. Complex T8a displayed moderate cytotoxicity against MCF-7 (IC50 = 40.69 (± 1.1) μM), while none of the other complexes displayed any anti-cancer activity at the complex concentrations tested. Subsequently, evaluation of the ligands against MCF-7 showed that ligands 1a – 4a displayed moderate cytotoxicity while 7a displayed anti-cancer activity (IC50 = 13.02 (± 1.2) μM) which is comparable to that of cisplatin. A structure-activity relationship in favour of the smaller N-bound substituents was established. DNA migration and titration studies revealed that ligands 1a – 4a displayed moderate intercalative character. Complex T8a displayed covalent binding in the DNA migration study, similar to that observed for cisplatin. Ligand 7a displayed weak intercalation based on the DNA migration study, but the DNA titration study revealed a potential multi-mode binding character. The affinity of the ligands towards DNA did not correlate directly with the IC50 values obtained. This potentially indicates that the pharmacological target of the cytotoxic ligands is probably not DNA, and thus requires further investigation.