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Design, Synthesis, and Biological Evaluation of Novel Histone Deacetylase Inhibitors as Anti-Cancer Agents

Al-Hamashi, Ayad Abed Ali Chiad A.
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525945712448479

Abstract Details

2018, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Despite major advances in cancer treatment strategies in recent years, significant limitations still remain. Selectively targeting cancer cells without affecting normal cells is a challenging task. Epigenetic modifications such as histone acetylation and methylation seem to play a crucial role in cancer pathophysiology. Histone acetylation is the most extensively studied epigenetic modification. Two groups of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation status of histones. HDAC enzymes, which are overexpressed in many cancer tissues, provide a potential target for cancer chemotherapy. Therefore, HDAC inhibitors are currently being widely investigated as anticancer agents. Most of the current HDAC inhibitors are not selective and have toxic side effects. Selective inhibition of specific HDAC isoforms to preferentially suppress the proliferation of cancer cells is a goal yet to be achieved. Largazole is a macrocyclic, depsipeptide anticancer agent isolated from a marine cyanobacterium. It is a class I selective HDAC inhibitor. The depsipeptide cap group (CG) of largazole interacts with a less conserved area of the HDACs surface and can be targeted to develop isoform-selective HDAC inhibitors. We have used molecular modeling approaches to design several new largazole analogs with modified CGs to modulate the binding interaction with the enzyme surface. We used a novel protection/deprotection protocol to synthesize these analogs. The antiproliferative activity and HDAC isoform selectivity of the synthesized analogs were evaluated. The majority of the clinically used HDAC inhibitors are hydroxamates. Poor selectivity, poor pharmacokinetics, and severe toxic side effects are major limitations in their clinical use. There is a high need to develop new HDAC inhibitors with non-hydroxamate zinc binding groups (ZBG) with superior activity and selectivity profiles. We used molecular modeling studies to design a new class of HDAC inhibitors containing a 1-(1H-imidazol-2-yl)ethan-1-one (HIE) moiety as the ZBG. A structure-activity relationship (SAR) study was conducted by synthesizing a series of HIEs with different structural properties. Some of these compounds showed promising cell growth inhibition with GI50s in the upper nanomolar to lower micromolar range. A representative HIE compound inhibited purified HDAC enzymes with single digit micromolar IC50, with no selectivity preference among different HDAC isoforms. Replacing the ZBG with other groups such as 1-(thiazol-2-yl)ethan-1-one (TE), 1-(pyrimidin-2-yl)ethan-1-one (PE), and 1-(2-hydroxyphenyl)ethan-1-one (HPE) did not result in active compounds.
Viranga Tillekeratne, Ph.D. (Committee Chair)
Amanda Bryant-Friedrich, Ph.D. (Committee Member)
Paul Erhardt, Ph.D. (Committee Member)
William Taylor, Ph.D. (Committee Member)
Donald Ronning, Ph.D. (Committee Member)
305 p.
Pharmacy Sciences
HDAC, Inhibitors, epigenetic, histone

Recommended Citations

Citations

  • Al-Hamashi, A. A. A. C. A. (2018). Design, Synthesis, and Biological Evaluation of Novel Histone Deacetylase Inhibitors as Anti-Cancer Agents [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525945712448479

    APA Style (7th edition)

  • Al-Hamashi, Ayad Abed Ali Chiad. Design, Synthesis, and Biological Evaluation of Novel Histone Deacetylase Inhibitors as Anti-Cancer Agents. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525945712448479.

    MLA Style (8th edition)

  • Al-Hamashi, Ayad Abed Ali Chiad. "Design, Synthesis, and Biological Evaluation of Novel Histone Deacetylase Inhibitors as Anti-Cancer Agents." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525945712448479

    Chicago Manual of Style (17th edition)

toledo1525945712448479
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This open access ETD is published by University of Toledo and OhioLINK.