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Synthesis and Biological Evaluation of HDAC Inhibitors with 1-(1H-imidazol-2-yl)ethan-1-one Moiety as the Metal-Binding Group

Dlamini, Samkeliso Mpendulo, Dlamini
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1501770195684609

Abstract Details

2017, Master of Science, University of Toledo, Medicinal Chemistry.
Synthesis and Biological Evaluation of HDAC Inhibitors with 1-(1H-imidazol-2-yl)ethan-1-one Moiety as the Metal-Binding Group By Samkeliso M Dlamini Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry The University of Toledo August 2017 Cancer is the second leading cause of death in the United States of America and the entire world and the disease burden is exacerbated due to resistance to drugs that are currently in clinical use. Histone deacetylase (HDAC) enzymes are highly expressed in cancer cells and HDACs are considered viable targets for drug intervention. HDACs cleave the acetyl groups from acetylated lysine side chains of proteins and modulate crucial cellular processes including gene expression. Four HDAC inhibitors (HDACi) have been approved by the US FDA as anticancer drugs for clinical use, but these drugs have numerous side effects due to low selectivity. This study presents an attempt to develop selective HDAC inhibitors using a novel metal-binding group as possible alternative to current cancer drug treatment options. In this study, molecular modeling studies were carried out using crystal models of four different HDAC isoforms to formulate novel HDAC inhibitors that have high selectivity. Designed HDACi analogs were studied to understand their mode of binding to HDAC active site, channel and the rim. Designed analogs, 14a-d and 15a-b were synthesized and evaluated for biological activity. The compounds were tested for anti-proliferative activity in the sixty human tumor cell line assay at the National Cancer Institute (NCI). Compounds 14a and 15a did not show significant cell growth inhibition at 10 ¿M and were therefore, not selected for dose response assay. Cells treated with 14b, showed 41% mean percentage growth at 10 ¿M, which amounts to 59% inhibition of the growth of the 60 cell lines. Compound 14c showed 21% mean percentage growth of cells at 10 ¿M, amounting to 79% growth inhibition of the 60 cell lines on average. Compound 14d was active with 24% mean percentage growth of the 60 cell lines, amounting to 76% mean inhibition of the 60 cell lines. Compound 15b was the most active and showed 19% mean percentage growth of cells at 10 ¿M, amounting to 81% growth inhibition of the 60 cell lines on average. Compounds 14b, 14c, 14d and 15b, showed significant cell growth inhibition at 10 ¿M concentration and were subjected to dose response assay at the NCI. Data from the dose response assay showed that the activity improves significantly when a chlorine atom or a trifluoromethyl group is installed at the para-position of the phenyl ring cap group. N-methylation of the imidazole ring did not cause a significant improvement in the activity response, but may be useful in modulating the pharmacokinetic properties of the molecules in preclinical development of the compounds as anticancer agents. This study shows that some of the compounds are more selective towards some cancer cell types. In preliminary biological studies, compound 14c was found to cause mitotic arrest of Hela cells. Further biological studies to elucidate the mechanism of action of these compounds are a future objective. This will complete the study and move our compounds to the next level of testing.
Viranga Tillekeratne (Committee Chair)
Li Wei (Committee Member)
James Slama (Committee Member)
William Taylor (Committee Member)
123 p.
Chemistry
HDAC; HDAC inhibitor; Zinc binding group; SAHA; Cancer

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Citations

  • Dlamini, Dlamini, S. M. (2017). Synthesis and Biological Evaluation of HDAC Inhibitors with 1-(1H-imidazol-2-yl)ethan-1-one Moiety as the Metal-Binding Group [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1501770195684609

    APA Style (7th edition)

  • Dlamini, Dlamini, Samkeliso. Synthesis and Biological Evaluation of HDAC Inhibitors with 1-(1H-imidazol-2-yl)ethan-1-one Moiety as the Metal-Binding Group. 2017. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1501770195684609.

    MLA Style (8th edition)

  • Dlamini, Dlamini, Samkeliso. "Synthesis and Biological Evaluation of HDAC Inhibitors with 1-(1H-imidazol-2-yl)ethan-1-one Moiety as the Metal-Binding Group." Master's thesis, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1501770195684609

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Toledo and OhioLINK.