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Synthesis of N-[Substituted Benzoylamino]-3-Ethyl-1,2,3,6-Tetrahydropyridines as Potential Anti-Inflammatory and Anticancer Agents
Başlık:
Synthesis of N-[Substituted Benzoylamino]-3-Ethyl-1,2,3,6-Tetrahydropyridines as Potential Anti-Inflammatory and Anticancer Agents
Yazar:
Henderson, Elizabeth D., author.
ISBN:
9780438009240
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (189 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Tiffany W. Ardley Committee members: John Cooperwood; Selina Darling-Reed; Bereket Mochona; Ebenezer Oriaku.
Özet:
The development of chronic inflammation is believed to promote cancer through cellular and genomic damage. The presence of inflammation creates a tissue microenvironment that enhances cell proliferation. According to the American Cancer Society, approximately 1,688,780 new cancer cases were expected to be diagnosis in the United States in 2017. While chemotherapy is the primary treatment option for cancer patients it is limited by its toxicity to normal cells. As a result, there is a significant need to develop compounds that are safer and have less adverse effects as potential anti-cancer agents.
Cyclooxygenase (COX) is an enzyme found to play an essential role in inflammation and converts arachidonic acid (AA) to prostaglandin-like (PG) molecules. Non-steroidal anti-inflammatory agents (NSAIDs) are non-selective COX inhibitors that target COX-1 and COX-2. While previous studies have demonstrated a correlation between NSAIDs use and decreased cancer risk, the adverse effects of NSAIDs remain problematic. COX-2 inhibitors were initially designed to reduce the adverse effects, which unfortunately remain insurmountable. Nitric oxide (NO) is a reactive oxygen species that plays a role in immunological response. Nitric oxide synthase (NOS) is the enzyme responsible for producing nitric oxide from L-arginine. NOS-2 and COX-2 are two major inflammatory mediators that are up-regulated in some cancers, such as breast cancer. As the search for safer and effective anti-inflammatory agents continues, the objective of this dissertation project is to design and synthesize tetrahydropyridines (THPs) as potential selective COX-2 inhibitors.
Previous studies have shown THPs are effective inhibitors of inflammation and cancer cell growth in vivo. The pharmacological activities of the THP derivatives depend mostly on the position and nature of the substituents on the THP ring structure. In an effort to design effective compounds with anti-inflammatory and anti-cancer activities, THPs with structural modifications were synthesized and their biological activities were determined.
Our approach was to design, synthesize, isolate, and purify the THP derivatives. Based on our preliminary findings that 3-ethyl THPs have COX-2 inhibitory activity, we hypothesized that the modification of the substituents on the THP derivatives will improve biological activity and enhance the antineoplastic properties of these novel agents. In order to explore our hypothesis, we will follow two synthetic schemes: 3-Ethylpyridine reacted with O-mesitylenesulfonyl hydroxylamine (O-MSH) or O-dinitrophenyl hydroxylamine (O-DNP) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gave the stable crystalline pyridinium ylides. A sodium borohydride reduction of pyridinium ylides furnished the target compounds N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines. Five novel N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines were synthesized.
Five THPs were synthesized and purified using column chromatography and crystallization. Elemental analysis, nuclear magnetic resonance (NMR), and infrared (IR) spectroscopy were used to confirm the identity of the THP analogs. 3,5-Dimethyl derivative inhibited NO activity. Four THPs (1-Naphthoyl, 3,4-Dimethoxy, 4-Iodo, and 3,5-Trifluoromethyl derivatives) were shown to be non-selective COX inhibitors. 3,5-Trifluoromethyl derivative showed some COX-2 selective activity. In the assessment of tetrahydropyridine's cytotoxicity on Ishikawa cells, MCF-7, and MDA-MB-231. The 4-Iodo derivative had IC50 values of 2.932, 1.25, and 5.67 muM respectively. These concentrations were lower than the reference compounds Tamoxifen and 4-Hydroxytamoxifen. Molecular modeling was performed using SYBYL-X 2.1 to determine the best structural conformations of the THPs for cyclooxygenase (COX-1 and COX-2) and estrogen receptor alpha (ERalpha). EH-1-22 had the highest docking score for COX-1 (-12.15) and COX-2 (-7.84). EH-1-27 had the highest docking score for ERalpha (-13.59).
The THP derivatives were successfully synthesized and characterized. Their structural and biological activities were determined. Although their activities varied, based on the data, 4-Iodo derivative emerged as a potential non-selective COX inhibitor with anti-cancer properties.
The research in this dissertation is significant because based on the preliminary results 4-Iodo derivative has anti-proliferative properties that are comparable if not better than Tamoxifen. This knowledge has implications of THPs being used for the treatment of cancer in the future.
Notlar:
School code: 0872
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678059.1) | 678059-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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