Exploration of novel 2,4-linked thiazole containing molecules as anti-cancer agents

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Abstract
This thesis describes the exploration of novel 2,4-linked thiazole containing molecules as anti-cancer agents via synthesizing natural product Marthiapeptide A and series of trithiazole containing molecules. The natural product Marthiapeptide A is a cyclic peptide that contains a unique trithiazole-thiazoline motif with D-alanine, D-phenylalanine, and L-isoleucine amino acid backbone. Given its novel structural features, potent anti-cancer activity and its limited availability from its source of isolation, synthesis of this natural product, and investigating the role of its trithiazole motif in anti-cancer activity were carried out in this study. My first project was aiming to develop a concise approach to accessing this natural product via total synthesis. In this project, two sites of ring closure were selected and investigated. The nitrile-cysteine heterocyclization reaction was used for thiazoline installation. Using a convergent synthesis approach the final natural product was successfully assembled. The identity of the final synthetic MTA-1 was confirmed matching with the natural product after extensive characterization including 1H NMR, 13C NMR, 2D NMR (COSY, HSQC, HMBC), variable temperature NMR, LC-MS, HR-MS, and LC co-inject analysis with the authentic natural product. My second project examined the structure-activity relationship of a series of novel trithiazole containing molecules, which retains the core structure in Marthiapeptide A but also mimic the key moiety in an established inhibitor RITA. I synthesized trithiazole containing molecules for anti-cancer mechanistic studies. While retaining the key feature of this compound, a 2,4-linked tri-thiazole backbone, I modified the terminal capping groups to include the following functionalities: ethyl ester, amide, amine, hydroxyl group. Subsequent modification of the single R group to methyl, isopropyl, benzyl methyl, cyclohexymethyl, and tetrahydroisoquinoline substituents was accomplished. I contributed 19 out of 44 molecules in this project. After successfully synthesizing target molecules, cytotoxicity screening was then carried out using HCT-116 human colon cancer cell lines to identify the most effective anticancer agents. After analyzing the most potent molecules for their GI50 values, cell cycle analysis and protein expression of c-Myc and Mcl-1were performed as compared to RITA. Our most active molecules were found exhibiting anti-cancer activity differently from RITA which suggests a different mechanism.
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Author(s)
Zhang, Yuqi
Supervisor(s)
McAlpine, Shelli. Renee
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Publication Year
2018
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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