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Jehad Almaliti - PhD thesis.pdf (5.55 MB)

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Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents

Almaliti, Jehad S.
http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204

Abstract Details

2013, Doctor of Philosophy in Medicinal Chemistry (Ph.D.), University of Toledo, College of Pharmacy.
Natural products are a prolific source of bioactive agents of diverse structure and varying biological activity. They are the single most productive source of lead molecules for developing clinically useful drugs for human disorders. Two different synthetic medicinal chemistry projects based on natural products were undertaken for my PhD research. The first research project focused on natural products-inspired synthesis of neuroprotective agents against H2O2-induced cell death. The second research project focused on the synthesis of novel largazole analogues targeting histone deacetylases to improve potency and isoform selectivity for treatment of cancer. Stroke is the fourth leading cause of death in the USA, where over 2000 new cases are diagnosed every day. Treatment options for stroke-related brain damage are very limited and there is an unmet need for effective neuroprotective agents to treat these conditions. Comparison of the structures of several classes of neuroprotective natural products such as limonoids and cardiac glycosides revealed the presence of a common structural motif which may account for their observed neuroprotective activity. Several natural product mimics that incorporate this shared structural motif were synthesized and were found to possess significant neuroprotective activity. These compounds enhanced cell viability against H2O2 induced oxidative stress or cell death in PC12 neuronal cells. The compounds were also found to enhance and modulate Na+/K+-ATPase activity of PC12 cells, which may suggest that the observed neuroprotective activity is mediated, at least partly, through interaction with Na+/K+-ATPase. Epigenetic regulation by altering gene expression without changing DNA sequences is a promising new strategy in developing anticancer agents. As histone deacetylases (HDAC) play an important role in gene expression, HDAC inhibitors have become an increasingly popular class of agents for targeting epigenetic regulation. Isoform and class-selective HDAC inhibitors are being developed to reduce the undesirable side effects resulting from non-selective HDAC inhibitory activity. Largazole is a potent and class I selective HDAC inhibitor recently isolated from a marine cyanobacterium of the genus Symploca. The depsipeptide ring of largazole constitutes the surface recognition cap group that interacts with the less conserved hydrophobic rim of the HDAC active site. In order to investigate the effect of the nature of this group on isoform and class selectivity, we have designed and synthesized largazole analogues with structural alterations in the depsipeptide ring (surface recognition cap group). In the designed analogues, the thiazole-thiazoline moiety of largazole is replaced with different aromatic and alkyl groups, to investigate the structure-activity relationship requirements. They include linear polyether group (analogue JA1), bi-pyridine group (analogue JA2), pyridine-methylamine group (analogue JA3), pyridine-benzylamine group (analogue JA4), pyridine-4-(trifluromethyl)benzylamine group (analogue JA5), and pyridine-4-methoxybenzylamine group (analogue JA6). The biological activities of the synthesized analogues JA1-JA6 are evaluated in the laboratory of Dr. Robert A. Casero, Jr. at the Johns Hopkins School of Medicine. The antiproliferative activity of analogues on HCT116 cells was evaluated using standard MTS reduction assay. The downstream effect of HDAC inhibition on global histone H3 acetylation has also been assayed using HCT116 cells. The isoform selectivity of the analogues is being determined using recombinant HDAC1, HDAC6, and HDAC8. The preliminary studies with analogue JA2 showed promising sub-nanomolar activity on many tumor cancer cell lines and is currently being further evaluated for synergistic activity with other clinically used anticancer agents. Additionally, analogues JA1-JA3 were found to be active at 10 µM in the 60 cell line human tumor screen at the National Cancer Institute (NCI) and they are currently being tested in the dose response assay.
L. M. Viranga Tillekeratne (Advisor)
Amanda Bryant-Friedrich (Committee Member)
Paul Erhardt (Committee Member)
Youssef Sari (Committee Member)
Zahoor Shah (Committee Member)
Chemistry; Pharmacology; Pharmacy Sciences

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Citations

  • Almaliti, J. S. (2013). Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204

    APA Style (7th edition)

  • Almaliti, Jehad. Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204.

    MLA Style (8th edition)

  • Almaliti, Jehad. "Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204

    Chicago Manual of Style (17th edition)

mco1384555204
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© 2013, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.