Design, syntheses and in vitro biological evaluation of polycyclic quinolones with potential anticancer activity

Garlapati, Ranjith (2013) Design, syntheses and in vitro biological evaluation of polycyclic quinolones with potential anticancer activity. Masters thesis, Memorial University of Newfoundland.

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Abstract

Cancer has long been known as a dreadful disease characterized by uncontrolled proliferation of tumor cells. Despite many breakthroughs in biotechnological fields and the discovery of various potent anticancer agents the need in chemotherapy is still unmet. Cancer develops by various mechanisms and the most common mechanism involves mutations in genes. Topoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase IT-targeting agents may benefit patients who prove resistant to currently available topoisomerase IT-targeting drugs or encounter unacceptable toxicities. Quinolones form an interesting group of molecules that have been intriguing the scientific world in recent years. The last few generations have seen the development of quinolone based drugs. They are well known for their activity against a broad spectrum of bacteria. Drugs such as ciprofloxacin, gatifloxacin, levofloxacin have stormed the clinical world within a short span of time. The last few years have witnessed the development of numerous novel tricyclics and tetracyclic quinolones that target mammalian topoisomerase I and II. The starting point of this research was a thiazoloquinolone which was patented by Kyorin/Kyowa-Hallo. This compound exhibited a promising cytotoxic profile in different animal models. -- Using Alchemy-3™, the optimum configuration of the patented compound was determined and based on this a linear tricyclic quinolone scaffold was designed and used in our research as a fundamental pharmacophore to synthesize novel molecules with antineoplastic profiles. -- This thesis is arranged into four chapters. The first chapter gives a brief history of cancer, quinolones and some of the classic synthetic reactions in the synthesis of 4-quinolones. Chapter 2 provides a review of anticancer quinolones structure-activity relationships and outlines the potential medical uses of quinolones apart from their classic use as antibacterial agents. Chapter 3 describes various aspects of synthetic procedures involved in the preparation of novel quinolone compounds and biological evaluation methods. Finally, chapter 4 concludes this thesis with a discussion of a possible future work. Thus, a number of thieno[2,3-b ]quinolones and the corresponding furoquinolones have been synthesized adapting conventional methods. The cytotoxicity screening of the target compounds was performed against HeLa and Kb cell lines. Unfortunately, the compounds have not shown reasonable activity.

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