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Synthesis and Biological Evaluation of New HDAC Inhibitors

Alqahtani, Abdulateef, Alqarni

Abstract Details

2018, Master of Science, University of Toledo, Medicinal Chemistry.
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 1-(1H-imidazol-2-yl) ethan-1-one moiety as 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 two different HDAC isoforms and HDLP to formulate novel HDAC inhibitors that have high selectivity. The designed analogs, 14a-g were synthesized and evaluated for biological activity. The compounds were tested for anti-proliferative activity in the NCI 60 cell lines assay. Compound 14a showed significant cell growth inhibition at 10 µM concentration with 87% mean cell growth inhibition. This compound was further tested in the dose response assay. It showed anti-proliferative activity in micro molar range against most of the cell lines while four leukemia cell lines were sensitive at sub-micro molar concentration of compound. Data from dose response assay showed that the activity improved significantly when a trifluoromethyl group is installed at the para-position of the phenyl ring cap group and with N-methylation of the imidazole ring According to docking studies of all seven compounds 14a-g on HDLP, compounds with N-methyl imidazole rings 14a-d showed flipping of the molecule in the HDAC active site, the acetamide oxygen binding to zinc ion with a high glide score instead of the keto-imidazole moiety. This is an important observation as the methylation at this position may be used to alter and modulate the pharmacokinetic and selectivity properties of the compounds for further development as anticancer agents. Compound 14c showed anti-cancer activity against Hela cells at 10 µM concentration, and anti-inflammatory activity on microglial cells at sub-micro molar concentration. Although the results of the preliminary studies for anti-inflammatory activity were promising, additional biological studies are needed to validate and confirm these results.
Viranga Tillekeratne, Ph.D. (Committee Chair)
James Slama, Ph.D. (Committee Member)
Zahoor Shah, Ph.D. (Committee Member)
114 p.

Recommended Citations

Citations

  • Alqahtani, Alqarni, A. (2018). Synthesis and Biological Evaluation of New HDAC Inhibitors [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525448898248748

    APA Style (7th edition)

  • Alqahtani, Alqarni, Abdulateef. Synthesis and Biological Evaluation of New HDAC Inhibitors. 2018. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525448898248748.

    MLA Style (8th edition)

  • Alqahtani, Alqarni, Abdulateef. "Synthesis and Biological Evaluation of New HDAC Inhibitors." Master's thesis, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525448898248748

    Chicago Manual of Style (17th edition)