Synthetic routes towards triazole cannabidiol analogues and substituted cycloparaphenylenes

Janse Van Rensburg, Mari (2019-12)

Thesis (MSc)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: Cancer is the leading cause of death worldwide and current treatment options often lead to painful and unpleasant side-effects. The active constituents isolated from medicinal plants have been successfully developed into various chemotherapeutic agents. The medicinal plant of interest in this research project, the cannabis plant, along with the constituents isolated, known as cannabinoids, have shown promising proapoptotic, anti-proliferative and anti-angiogenic effects. Interest in non-psychoactive cannabinoids, in particular cannabidiol (CBD), has significantly increased in recent years. CBD offers the hope of improved anticancer therapies that selectively target cancer cells without affecting normal cells, thereby eliminating the unwanted side-effects associated with conventional therapies. This project involved the design and synthesis of CBD analogues by mimicking the main pharmacophoric groups found on the structure of CBD. The main difference between the natural occurring cannabinoid and the analogues in this study, was the replacement of the benzene ring at the core of the structure with a 1,2,3-triazole ring using click chemistry. A triazole moiety can provide improved solubility and bioavailability, while helping to exploit the chemical space around the compound. Three different systems (Scaffold A, B and C) were explored throughout this project. The transitions between these systems involved systematic alterations of functional groups on the general structure of each system, as well as the introduction of stereochemistry in the synthesis of Scaffold C. Important reactions used during the synthesis of these scaffolds included an epoxide ring opening via nucleophilic substitution, a Michael reaction, an Appel reaction, a nucleophilic substitution reaction resulting in an inversion of stereochemistry, as well as copper- and ruthenium-catalyzed azide alkyne cycloaddition reactions. These reactions provided the 1,4- and 1,5-, as well as 1,4,5-polysubstituted 1,2,3-triazole CBD analogues. The anticancer activity of these compounds was subsequently evaluated against the MCF-7 cell line, as well as the HeLa cell line. None of the CBD triazole analogues of this study showed particularly appealing activity against these cancer cell lines. One analogue did however show potentially interesting activity against the MCF-7 cell line, and two analogues had an IC50 value below 100 μM against the HeLa cell line, with the most promising analogue providing an IC50 value of 74.3 μM. In addition, all compounds tested were completely devoid of toxicity below concentrations of 100 μM. The results obtained provide valuable insight into the future design of triazole CBD analogues. The synthesis of complex macrocycles and the study of the structural characteristics and properties displayed by these compounds is a fascinating research field. Cycloparaphenylenes (CPPs) are macrocycles which consist of benzene rings connected through para-linkages. This project focused on the synthesis of functionalized CPPs as these macrocycles could provide new host−guest possibilities, possible use in chemosensors and nanoporous materials and the option of connecting these CPP macrocycles to various surfaces. A method was developed for the synthesis of substituted [8]CPPs containing a thioether functionality, which provides the option of effortlessly transforming the substituents throughout the synthesis to give access to the previously synthesized ether-containing [8]CPP macrocycle. The series of reactions used during the synthesis of this CPP linker system included a Sonogashira coupling reaction, a dibromination reaction and a macrocyclization reaction, among others. A linear test system was developed with a similar backbone structure to the substituted CPPs. The synthesis of the linear test system allowed investigation of the optimum route for the formation of the thioether functionality, which was then directly applied to the CPP linker system to gain access to the sulfur-containing CPP macrocycle.

AFRIKAANSE OPSOMMING: Kanker is tans wêreldwyd die hoofoorsaak van sterftes. Die verskeie vorme van behandeling wat beskikbaar is lei dikwels tot pynlike en onaangename newe-effekte. Die aktiewe komponente, wat van medisinale plante verkry is, is reeds suksesvol tot verskeie chemoterapeutiese middels ontwikkel. Die medisinale plant in hierdie navorsingsprojek ter sprake, is die cannabis plant, asook die komponente, kannabinoïede, wat uit hierdie plant geïsoleer is. Dit toon belowende proapoptotiese, anti-proliferatiewe en anti-angiogeniese effekte. Belangstelling in nie-psigoaktiewe kannabinoïede, in besonder kannabidiol (CBD), het aansienlik verhoog in die afgelope paar jaar. CBD bied hoop op verbeterde anti-kankerterapieë, wat kankerselle selektief teiken, sonder om normale selle te beïnvloed. Dit skakel dus die ongewenste newe-effekte, geassosieer met konvensionele terapie, uit. Hierdie projek behels die ontwerp en sintese van CBD analoë deur die farmakoforiese groepe, wat in die struktuur van CBD gevind word, na te boots. Die hoof verskil tussen die kannabinoïd wat natuurlik voorkom, en die analoë in hierdie studie, is die vervanging van die benseenring, in die kern van die struktuur, met ʼn 1,2,3-triasool ring, deur middel van kliek chemie. ‘n Triasool komponent kan verbeterde oplosbaarheid en biobeskikbaarheid bied, terwyl dit terselfdertyd help om die chemiese spasie rondom die verbinding te benut. Drie verskillende sisteme (Steier A, B en C) is tydens hierdie projek ondersoek. Die oorgang tussen sisteme behels die sistematiese wysiging van funksionele groepe op die algemene struktuur van elke sisteem, sowel as die invoer van stereochemie in die sintese van Steier C. Belangrike reaksies wat tydens die sintese van die steiers gebruik is sluit in ʼn epoksied ring-opening, deur middel van nukleofiele vervanging, ʼn Michael-reaksie, ʼn Appel-reaksie, ʼn nukleofiele vervangingsreaksie wat lei tot ‘n inversie van stereochemie, asook koper- en rutenium-gemedïeerde azied alkyn sikloaddisie reaksies. Hierdie reaksies het die 1,4- en 1,5-, sowel as 1,4,5-gesubstitueerde 1,2,3-triasool CBD analoë verskaf. Die anti-kanker aktiwiteit van hierdie verbindings is vervolgens teen die MCF-7 sellyn, asook die HeLa sellyn, geëvauleer. Geen van die CBD triasool analoë in hierdie studie het besondere belowende aktiwiteit teen die twee sellyne getoon nie. Een verbinding het egter potensieël interessante aktiwiteit teen die MCF-7 sellyn getoon en twee analoë het ʼn IC50 waarde minder as 100 μM, teen die HeLa sellyn gehad. Die mees belowende analoog het ‘n IC50 waarde van 74.3 μM verskaf teen die HeLa sellyn. Daarbenewens is alle verbindings wat getoets is, heeltemal vry van toksisiteit onder konsentrasies van 100 μM. Die resultate verskaf waardevolle insig in toekomstige ontwikkeling van triasool CBD-analoë. Die sintese van kompleks makroringe, asook die studie van die strukturele kenmerke en eienskappe wat hierdie verbindings toon, is ʼn baie interessante navorsingsveld. Sikloparafenilene (CPPs) is makroringe wat bestaan uit benseenringe wat deur para-skakeling verbind word. Hierdie projek fokus op die sintese van gefunksioneerde CPPs omdat hierdie makroringe nuwe gasheer-gas moontikhede, moontlike gebruik in chemosensors en nano-poreuse materiale, asook die opsie om hierdie CPP makroringe met verskeie ander oppervlaktes te verbind, kan bied. ʼn Metode is ontwikkel vir die sintese van gesubstitueerde [8]CPPs wat n tioeter funksionaliteit bevat, wat die opsie bied om die substituente deur die loop van die sintese te transformeer om toegang tot die vorige gesintetiseerde eter-bevattende [8]CPPs te verskaf. Die reeks reaksies wat tydens die sintese van hierdie CPP skakelsisteem gebruik is, sluit ‘n Sonogashira-koppelingsreaksie, ʼn dibrominasie-reaksie en ʼn makrosikloserings-reaksie, onder andere, in. ʼn Lineêre toetssisteem is ontwikkel met ʼn soortgelyke ruggraatstruktuur as die gesubstitueerde CPPs. Die sintese van die lineêre toetssisteem het die geleentheid gebied om die optimale roete vir die formasie van die tioeter funksionaliteit te ondersoek, wat toe direk op die CPP skakelsisteem toegepas is om toegang tot die swael-bevattende CPP makroring te verkry.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/106994
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