Date of Award
Zhe Sheg Chen
Cancer has been plaguing the humanity for several decades. In the meanwhile, multi-drug resistance (MDR) is causing abatement of effective therapeutic drugs, necessitating discovery of new class of anticancer agents. Natural products have been proved to be a promising source of structurally new anticancer agents. A specific class of bacterial secondary metabolites, named siderophores have been explored as potential anticancer agents. Enterobactin is one of the most studied siderophores as a potential anticancer agent. Azotochelin is a structurally similar but structurally simpler siderophore compared to enterobactin. Our research project focused on the evaluation of the structure activity relationship assessment of azotochelin for its anticancer activity as well as inhibitory activity against ABC transporters. We synthesized libraries of analogs by incorporating structural modifications at carboxylic acid, aromatic rings, linker and catechol of the azotochelin and screened their cytotoxicity against a panel of cancer cell lines. Natural azotochelin (4) exhibited cytotoxicity towards various cancer cell lines with an IC50 range of 5.8 - 87 M. After an initial assessment of the functional group requirements, we synthesized a series of metabolically stable amide analogs of azotochelin. Several of the benzylamide analogs were selectively cytotoxic towards cancer cells. Compound 39 was found to be most potent from benzylamide series with an IC50 value of 0.80 ± 0.01 uM against NCI-H460 cell line. The phenethylamide series turned out to be selectively most potent series, all the compounds showed IC50 <10 uM with sub-micromolar IC50 for most of the compounds in NCI-H460 cell line. Modifications at aromatic rings led to a selectively potent compound (61) with an IC50 value of 0.80 ± 0.10 uM. We attempted to evaluate the ability of the most potent compounds to interfere with the cell cycle using flowcytometry, however the initial results are inconclusive. As part of a second project, we synthesized and tested a library of compounds against two ABC transporters, ABCB1 and ABCG2. We found that compounds 73 and 85 modulated the activity of ABCB1 transporter with resistance folds of 12 and 15.9 respectively at 10 uM concentration of the test compounds. Similarly, compounds 19, 59, 73 modulated the activity of ABCG2 transporter with resistance folds of 23, 30 and 17 respectively at 10 uM concentration of the test compounds.
Karadkhelkar, Nishant, "CHEMICAL SYNTHESIS AND EVALUATION OF AZOTOCHELIN ANALOGS AS ANTICANCER AGENTS AND THEIR ABILITY TO REVERSE ANTICANCER DRUG RESISTANCE" (2020). Theses and Dissertations. 382.
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