Browsing by Author "Taleli, Lebusetsa"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Synthesis of polymer-bound small-molecule kinase inhibitors as anti-tumour agents
    (Stellenbosch : Stellenbosch University, 2017-12) Taleli, Lebusetsa; Klumperman, Bert; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Inhibition of kinase activities using small molecules for the treatment of various diseases, including lung cancer, is one of the most pursued therapeutic targets. Molecularly targeted therapy aimed at the inhibition of specific protein kinase signalling activities, e.g. epidermal growth factor receptor (EGFR), has changed the treatment landscape of clinical oncology into personalised medicine. Today, lung cancer patients are stratified according to tumour genetic mutations and are further profiled into kinase inhibitor treatment options. The 4-anilinoquinazoline class of small molecules are EGFR kinase inhibitors, used for the treatment of adenocarcinoma NSCLC. Therapeutic challenges affecting the efficacy of these molecules include low bioavailability, off-target reactive toxicities, and acquired drug resistance. The core objective of this study was to investigate the formulation of 4-anilinoquinazoline small molecules into polymer-drug conjugates. These conjugates were intended for use in a micellar drug delivery mechanism using poly(N-vinylpyrrolidone) (PVP) and pHresponsive linker groups. The 4-anilinoquinazoline anti-tumour agents carrying Michael acceptor electrophiles (acrylamide and acrylates) were synthesised by assembling various quinazolin-4(3H)-one derivatives. The preparation of a PVP delivery carrier was achieved by means of triazole-based RAFT/MADIX polymerisation. The ɷ-end group transformation of PVP into a thiol functionality was realised by aminolysis and the polymer-drug conjugates were then developed by 1,4-conjugated Michael addition reaction. The conjugates were allowed to self-organise into characteristic micelles in aqueous solutions. Assessments of the drug release profiles under variable pH conditions showed that release is favoured in the acidic tumour microenvironment. Furthermore, the in vitro anti-tumour efficacy of the amide-linked conjugate was demonstrated to match the Gefitinib ATP-competitive EGFR kinase inhibitor against EGFR wild-type and EGFR L858R/T790M mutant. The overall anti-tumour efficacy suggests that the mode of EGFR kinase inhibition is a critical determinant of anti-tumour efficacy. Further developments related to the present formulation are however necessary to enhance bioactivities of the conjugates.
  • Thumbnail Image
    Item
    Synthesis of triazole-linked chloroquinoline derivatives as novel antimalarial agents
    (Stellenbosch : Stellenbosch University, 2013-03) Taleli, Lebusetsa; Van Otterlo, William A. L.; Blackie, Margaret A. L.; Pelly, Stephen; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    Aminoquinolines are important class of drugs that have been used for malaria chemotherapy for centuries. However, long-term exposure to these drugs leads to extensive spread of drug resistance. As such, modified chloroquinoline derivatives are being studied as alternative antimalarial agents with the possibility to overcome drug resistance associated with chloroquine analogues. In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazole ring to an ethyl and propyl carbon spacer with a distal amine motif were designed and synthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. The compounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyne precursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncoupling in the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). These compounds have been characterized by the combination of NMR, ESI+ HRMS and IR spectroscopic methods. The antiplasmodial activity of the compounds was investigated in vitro against P. falciparum strain NF54 using chloroquine as a reference drug together with a standard antimalarial drug artesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possess promising potency by way of the inhibition concentrations less than 250 nM with the lowest being 28 nM. The observed activities have been ascribed to the overall modifications such as the introduction of a triazole linker and changing of carbon chain length as these were the variables. The compounds are accordingly under further biological investigations and only the chloroquine sensitive results are reported in this work.