Synthesis and biological studies of benzofuran-based estrogen receptor α modulators, pyridone alkaloids and zanamivir

• Main Author: Leow, Min Li
• Other Authors: Liu Xuewei
• Format: Theses and Dissertations
• Language: English
• Published: 2014
• Subjects: DRNTU::Science::Chemistry::Organic chemistry::Organic synthesis
• Online Access: http://hdl.handle.net/10356/55776
• Institution: Nanyang Technological University

In the first chapter, the search for new estrogen receptor alpha (ERα) modulators commenced with a trial molecular screening and 5,6-dihydroxybenzofuran was identified as a possible drug target for ERα. The target molecular modelling compound and a series of 5,6-dihydroxybenzofurans were synthesized and evaluated for their anti-proliferation activities against MCF-7 and MDA-MB-231 breast cancer cells. From the Structure-Activity Relationship (SAR) studies, potential functional groups were identified. The two hydroxyl groups at C-5 and C-6 and the phenyl ring at C-2 positions were found to influence the bioactivity significantly, as considerable cytotoxicity was observed in MCF-7 breast cancer cells. In addition, the apoptotic abilities of the compounds were measured in both MCF-7 (ER+) and MDA-MB-231 (ER-) cells. The results demonstrated that our compounds inhibit MCF-7 breast cancer cells via ER+. These preliminary results provide valuable information towards the identification of important functional groups present on 5,6-dihydroxybenzofuran, which could potentially be a promising scaffold for designing novel ER ligands. Chapter 2: Total Synthesis of Pyridone Alkaloids with Antiproliferation Activities In the second chapter, the total synthesis of pyridone alkaloids, specifically pretenellin B, prebassianin B, farinosone A, militarinone D, pyridovericin and torrubiellone C has been synthesized using a combination of convergent and divergent approach, which differ in their R1 chain. Interestingly, in a preliminary screening of these pyridone alkaloids for bioactivities of pharmaceutical interest, cell proliferation assay conducted on five tumor cell lines resulted in the identification of distinct and apoptotic inhibitory properties on Jurkat T-cells. Hence, the preliminary data obtained suggests the possibility of 2-pyridone as a new scaffold for acute lymphoblastic leukemia cells. Chapter 3: Synthesis of Zanamivir In the final chapter of the thesis, the synthetic strategy to zanamivir is presented. The key step involves a one pot sequential rhodium catalyzed aziridination, Barbier allylation of D-glucal and an amine to provide a stereoselective eight membered ring amino-oxathiazocane and subsequently provides an expedient access to zanamivir. This synthetic approach enables the use of cheap and readily available D-glucal as starting material and does not involve explosive azide for reaction. Hence, the development of this synthetic route would be highly beneficial to the pharmaceutical and industrial sectors.