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

Buys, Jaques (2017-12)

Thesis (MSc)--Stellenbosch University, 2017.

Thesis

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 contribute as it interacts with DNA. The DNA binding studies preliminarily indicate that these compounds interact with the DNA structure, meaning it has good potential as anti-cancer agents.

AFRIKAANSE OPSOMMING: Die hoë sterftesyfer van kanker wêreldwyd, was die dryfkrag agter hierdie navorsingsprojek. Ons doel was om geskikte radiofarmaseutiese molekules te sintetiseer wat moontlik as anti-kanker beeldings-agente kan optree. Dit behels die sintese van nuwe sikliese-kern dendrimere asook die funksionalisering van hul oppervlak groepe om selektiewe interaksie met hidroksieapatiet (HAp) te bevorder, wat 'n algemene teiken vir beeldings-agente vir beenkanker is. Hierdie dendritiese ligande moet ook as 'n steier vir "koue" radiofarmaseutiese analoëe kan funksioneer. Dendrimere vertoon verskillende fisiese en chemiese gedrag gebaseer op hul bestandele, dus was 1,4,8,11-tetrasasiklotetradekaan (siklam) en 1,4,7-triazasiklononaan (TACN) gekies as kernmolekules om die algehele topologie van die makromolekule te verander. Verskeie sintetiese pogings wat die gebruik van siklam-kern poliamidoamien (PAMAM) dendrimere, TACN-kern PAMAM-dendrimere asook siklam-kern polipropyleenimien (PPI) en siklam-kern bensielamien (BA) dendrimere, word aangemeld. Tydens die syntese van die PAMAM dendrimere (D1 - D6) het sommige komplikasies tydens die amidasiestap ons verbied om hoër generasie dendrimere te isoleer, dus is die alternatiewe PPI- en BA-vertakte dendrimerers (D7 - D10) gekies om die verskillende dendrimere te vergelyk. Laasgenoemde gaan via 'n nitriel intermediêr, gevolg deur reduksie wat dendrimere met primêre amien groepe op die periferie bied, maar volledige nitril reduksie het ons ontwyk. Generasie 1 siklam-kern PAMAM-dendrimere (D2) is as 'n geldige kandidaat geïdentifiseer om te funksionaliseer met fosfonsuur of salisielaldimien. Die fosfonsuur analoog (L1) is verkry via 'n Irani-Moedritzer reaksie. Deur soortgelyke reaksietoestande toe te pas, was 'n stel model ligande gebaseer op propielamien (ML1-ML2) en kommersiële diaminobutaan (DAB) PPI-dendrimer (L2) gesintetiseer vir vergelyking met L1. Die ligande was gewoonlik higroskopies van aard en onder die reaksietoestande het die interne amied van PAMAM bewyse van hidrolise getoon. Twee galium (III) komplekse (C1 en MC1) is van L1 en ML1 geïsoleer. Die salisielaldimien-analoog (L3) was gesintetiseer via 'n Schiff-basis kondensasie reaksie. Die ligand was gebruik om twee galium (III) komplekse (C4a en C4b), sowel as 'n koper (II) kompleks (C5) te isoleer. Die bogenoemde molekules was gekaraktiseer deur 'n verskeidenheid analitiese tegnieke (FT IR, UV Vis en NMR spektroskopie, massaspektrometrie en elementêre analiese). Die salisielaldimien analoog (L3) sowel as die galium (C4a en C4b) en koper (C5) afgeleides was onderworpe aan voorlopige DNA bindings studies via UV/Vis spektroskopie titrasie eksperimente. L3 en C4b het hiperchromie vertoon wat dui op groef bindende interaksie met DNA. Aan die ander kant het C5 'n hipochromiese effek vertoon wat interkalasie impliseer as die manier van bind met DNA. Verbasend genoeg toon C4a wisselende hiper- en hipochromiese effekte, wat insinueer dat daar verskillende bindingswyses bydra tot die interaksie met DNA. Die DNA bindende studies dui voorlopig aan dat hierdie molekules met DNA bind, en dat dit goeie potensiaal as anti-kanker agente het.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/102833
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