Design and development of novel irreversible GSK-3β inhibitors to address Alzheimer's disease

Hamann, Anton Ruben (2018-03)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Molecular modelling on the GSK-3β protein was carried out to identify a library of suitable electrophilic warhead containing ligands that have the necessary interactions with the binding site. Several series of novel irreversible inhibitors for GSK-3β with potential anti-Alzheimer‟s disease activities were then synthesised. In total, eleven compounds were successfully synthesised. The compounds have been fully characterised using standard spectroscopic and analytical techniques. The scaffold, 5-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}pyrazin-2-amine, was equipped with an α,β-enone Michael acceptor, that allowed for the coupling of various side chains using substitution chemistry. A library of two different series with an internal Michael acceptor was synthesised. The synthesis of the third series that consisted of a terminal Michael acceptor or a halomethylketone was attempted but proved futile. Suzuki-Miyaura chemistry has been thoroughly explored to find the best conditions to offer the products in acceptable yields. Pd(dppf)Cl2 as a catalyst, in a solvent system of toluene:ethanol:water, was found to be the best candidate for the Suzuki-Miyaura reactions to synthesise the aforementioned scaffold. The compounds were tested against the human recombinant GSK-3β and were found to have weak to good activity (GSK-3β IC50 range: 0.12 - >10 μM). The most active compound (GSK-3β IC50: 0.12 μM) consisted of a pyridine ring and the carbonyl of the Michael acceptor is situated directly next to the aminopyrazine core. The results showed that the libraries have the potential to be expanded into a second generation of new compounds.

AFRIKAANSE OPSOMMING: Deur gebruik te maak van molekulêre modellering was verskeie nuwe reekse onomkeerbare inhibitore vir GSK-3β gesintetiseer wat potensiële aktiwiteit bevat vir die bestryding van Alzheimer se siekte. Elf molekules was suksesvol gesintetiseerd en volledig gekarakteriseerd met behulp van spetroskopiese en analitiese tegnieke. Die raamwerk, 5-{4-[(4-metielpiperasien-1-iel)sulfoniel]feniel}pyrasien-2-amien, was verbind aan „n elektrofiliese “lokval”. Verskeie sykettings was dan gekoppel deur gebruik te maak van SN2 substitusie. Twee reekse molekules met „n interne α, β-enoon Michael ontvanger is gesintetiseer. Die sintese van die derde reeks wat „n terminale Michael ontvanger of „n halometielketoon bevat, het probleme opgelewer en was nie suksesvol nie. Die Suzuki-Miyaura chemie was deeglik ondersoek om die beste kondisies te vind wat die produkte in aanvaarbare opbrengste sal lewer. Pd(dppf)Cl2 as katalis in „n oplosmiddel sisteem van tolueen:etanol:water was bepaal as die beste kandidaat vir die Suzuki-Miyaura reaksies om die bogenoemde raamwerk te sintetiseer. Die molekules was getoets op die menslike rekombinante GSK-3β en die aktiwiteite was bepaal as matig tot goed (GSK-3β IC50 reeks: 0.12 - >10 μM). Die mees aktiefste molekuul (GSK-3β IC50: 0.12 μM) bevat „n piridien ring en die karboniel van die Michael ontvanger is direk gekoppeld aan die aminopiperasien kern. Die resultate het ook gewys dat die molekules die potensiaal het om onomkeerbaar te bind aan GSK-3β. Gebaseerd op die positiewe resultate, het die reekse ook die potensiaal om verder uitgebrei te kan word.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/103901
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