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Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents

Sindi, Shaimaa Hesham
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1564676186975875

Abstract Details

2019, Master of Science, University of Toledo, Medicinal Chemistry.
It is evident that epigenetics plays an important role in gene regulation. Consequently, any disruption in epigenetic memory will manifest into gene expression and lead to long-established transformation events. Covalent modification of histone is one of the epigenetic regulation mechanisms, and includes acetylation, methylation, phosphorylation, and ubiquitylation among others. Combination of two or more of these modifications acts like a sensor for gene expression or gene repression through highly condensed or uncondensed chromatin structures. The cancer epigenome is specifically marked with global DNA methylation and histone alteration patterns. The gene regulation is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation through HATs results in expansion of chromatin, and thus increases the accessibility of transcription factors to DNA. On the other hand, the deacetylation with HDACs leads to very condensed chromatin structures and consequently, to transcription repression. Owing to their specificity for cancer cells, HDAC inhibitors have now become a powerful target in anticancer drug development. The pharmacophore of HDAC inhibitors consists of a zinc-binding group, a linker and a capping group. These drugs exert their effect on cancer cells by arresting them in G1 or G2-M phases of the cell cycle, or by induction of differentiation and apoptosis. They can also inhibit angiogenesis and metastasis and regulate the host immune response. Generally, HDACs can be classified into four different classes (class I, II, III, and IV). It is well established that most HDAC inhibitors in clinical use lack specificity. It is believed that variations in the nature of the capping group can lead to variations in HDAC inhibitory activity and isoform selectivity. Our group has successfully developed a new class of HDAC inhibitors incorporating an imidazole ketone moiety as the capping group. Cytotoxicity studies of these molecules have shown promising activity. Efforts are underway in our laboratory to modulate the activity and selectivity of these compounds by changing the capping group. Guanidines have been reported to possess a wide range of biological activity. The biochemical and biophysical properties of guanidine are partly attributed to their specific hydrogen bonding, Y aromaticity, and pi-stacking properties. A molecule with such properties is able to bind to carboxylates, phosphates and metals. In this study, several HDAC inhibitors with imidazole ketone metal-binding group and guanidine moieties as the capping group were designed for synthesis and methods for making versatile cyclic guanidine molecules to be used in the synthesis of HDAC inhibitors were developed. In addition, two HDAC inhibitors incorporating guanidine moieties were synthesized. One of the analogues showed potent cytotoxic properties in the NCI 60 cell line assay with a mean growth inhibition of 64.5% and GI50 values in the low micro molar range against some cell lines. The cytotoxic activity of the compound was confirmed in studies performed in the laboratory of Dr. William Taylor of the biological Sciences Department. The other compound did not show activity in studies carried out in Dr. Taylor’s lab and is yet to be tested at NCI for its cytotoxic activity. The incorporation of other guanidine moieties in to target molecules proved problematic, probably due to poor nucleophilicity of their amine groups. However, synthesis of these target molecules using different reaction conditions and changing synthetic design is currently in progress.
L.M. Viranga Tillekeratne (Committee Chair)
James Slama (Committee Member)
Katherine Wall (Committee Member)
Zahoor Shah (Committee Member)
131 p.
Chemistry; Pharmaceuticals; Pharmacy Sciences
Cancer; HDAC; guanidine

Recommended Citations

Citations

  • Sindi, S. H. (2019). Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1564676186975875

    APA Style (7th edition)

  • Sindi, Shaimaa. Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents. 2019. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1564676186975875.

    MLA Style (8th edition)

  • Sindi, Shaimaa. "Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents." Master's thesis, University of Toledo, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1564676186975875

    Chicago Manual of Style (17th edition)

toledo1564676186975875
308
© 2019, some rights reserved.Creative Commons License Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents by Shaimaa Hesham Sindi is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo and OhioLINK.