Abstracts Category : Other

The development of low generation cyclic-cored metallodendrimers for potential application in anti-cancer therapy

by Jaques Buys

ENGLISH ABSTRACT: The high mortality rate of cancer worldwide was the impetus for this research project. Our aim was to synthesize suitable radiopharmaceuticals that could potentially act as anti-cancer imaging agents. This entails the synthesis of novel cyclic-cored dendrimers as well as their functionalization at the peripheries, in order to promote selective interaction with hydroxyapatite (HAp), which is a common target for bone cancer imaging agents. These dendritic ligands should also be able to act as a scaffold for cold radiopharmaceutical analogues.Dendrimers exhibit different physicochemical behavior based on their constituents, thus 1,4,8,11-tetraazacyclotetradecane (cyclam) and 1,4,7-triazacyclononane (TACN) were chosen as core molecules to alter the overall topology of the macromolecule. Several attempts describing the synthesis of cyclam-cored poly(amidoamine) (PAMAM) dendrimers, TACN-cored PAMAM dendrimers as well as cyclam-cored polypropylenimine (PPI) and cyclam-cored benzyl amine (BA) dendrimers is reported. During the PAMAM dendrimer (D1 - D6) synthesis some complications during the amidation step prohibited us from acquiring higher generation dendrimers, thus the alternative PPI and BA branched dendrimers (D7 - D10) were chosen in order to compare the effect of the various dendrimers employed. The latter goes via a nitrile intermediate followed by reduction to afford primary amine terminated dendrimers, but complete nitrile reduction eluded us.Generation 1 cyclam-cored PAMAM dendrimers (D2) was identified as a viable candidate to functionalize with either phosphonic acid or salicylaldimine chelators. The phosphonic acid analogue (L1) was obtained via an Irani-Moedritzer reaction and using similar reaction conditions a set of model ligands based on propyl amine (ML1 - ML2) and commercial diaminobutane (DAB) PPI dendrimer (L2) was synthesized for comparison with the multinuclear derivative. The ligands were usually hygroscopic in nature and under the employed reaction conditions the internal amide of PAMAM showed some evidence of hydrolysis. Two gallium (III) complexes (C1 and MC1) was isolated from L1 and ML1. Alternatively, the analogous salicylaldimine ligand (L3) was synthesized via a Schiff base condensation reaction. The relative simplistic ligand was used to isolate two gallium (III) complexes (C4a and C4b) as well as a copper (II) complex.(C5). These compounds were characterized by a range of analytical techniques (FT IR, UV Vis and NMR spectroscopy, mass spectrometry and elemental analysis).The salicylaldimine analogue (L3) as well as the gallium (C4a and C4b) and copper (C5) derivatives were subjected to preliminary DNA binding studies via UV vis spectroscopy titration experiments. L3 and C4b exhibited hyperchromism suggestive of groove binding interaction with DNA. On the other hand, C5 displayed a hypochromic effect implying intercalation as the mode of binding with DNA. Surprisingly C4a showed varying hyper- and hypochromic effect insinuating various binding modes contributeAdvisors/Committee Members: Malgas-Enus, Rehana, Mapolie, Selwyn, Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science..