Abstract
Chapter 1: Topoisomerases- Structures, Inhibitors, Dual Inhibitors and the Natural Quinazolinones as Topo Inhibitors. Every reaction that occurs in biological systems is catalyzed by an enzyme. The interconversions of the different topological forms of DNA are no exceptions. The enzymes that catalyze these processes are known as DNA topoisomerases I and II (called TOPOS) and constitute a widespread and fascinating group of anti-cancer drug targets. In the first chapter of the thesis, we will provide introduction and discussion of the structures of a number of topoisomerase fragments, representing nearly all the known classes of enzymes, which will provide remarkable insights into the mechanisms of these enzymes and complement previous conclusions based on biochemical analyses. However,over acting of the topoisomerases courses many problems on the cell such as Cancer, due to this reason we need to enter drugs to the cell that they can inhibit the over activity,called topoisomerases I and II inhibitors. Currently when one type of topoisomerase is inhibited, the levels of the uninhibited protein rise. Some strains of cancer are also known to develop resistance to single topoisomerase inhibitors. So, there is a need for dualtopoisomerase inhibitors that can address these needs of targeting of this proven drug targets. This chapter is co-written with Ron Mastrolia, another graduate student, hence there is overlap in the treatise. Chapter 2: Quanzolinones- Properties, Previous studies and Our Efforts Towards Synthesis of 4(3H)-Quinazolinones. Drug discovery and optimization constitutes one of the most important aspects of medicinal chemistry. Heterocyclic chemistry is the very important branch of organic chemistry. Heterocyclic chemistry comprises at least half of all organic chemistry research worldwide. In particular, heterocyclic structures form the basis of many pharmaceutical, agrochemical and veterinary products. There are numerous biologically active molecules whose framework includes a six-membered ring containing two nitrogen atoms fused to a phenyl ring. Quinazolinones have emerged as an important class of such nitrogenated heterocycles attracting significant synthetic interest because of their pharmacological and therapeutic properties such as: anti-parasitic, anti-tumor, antibacterial,anti-fungal, anti-inflammatory, anti-viral, and anti-cancer activities. In addition,large numbers of quinazolinone alkaloids have been isolated from a number of plants,animals and microorganisms and synthesized in view of their well-established pharmacological activities. This chapter portrays a concise account on isolation, bioactivity, reactions of Quinazolinones and examples of marketed drugs that contain Quinazolinone core as the pharmacophore. Their ubiquitous presence demands simple synthetic methods for their preparation to facilitate their facile incorporations in medchem programs and to further pharmacological studies. In the second chapter, we review the previous synthetic methods that have utilized formamide, orthoformate, various metal catalysts, and microwave technology. We also provide an account of our studies. We have achieved good yields of mono-substituted quinazolinones through a novel reaction of anthranilamide and aldehyde using sodium bisulfite and DMF as reaction medium. This strategy is very simple and it gives us the pure Quinazolinone in a high yield withoutneed for purification. We employed this method to rapidly bring in the complexity of the natural products like substituted quinazolinones. Chapter 3: Synthesis of Fused Quinazolinone Natural Product Like Scaffolds. Fused quinazolinone heterocyclic alkaloids have attracted high attention inorganic and medicinal chemistry due to their significant and wide range of biological activities. There are approximately 200 naturally occurring quinazolinone alkaloidsknown till 2015. Fused quinazolinones are important pharmacophores as privileged structures in medicinal chemistry and are of great pharmaceutical value. These structures represent molecules which are capable of binding at multiple sites with high affinity and facilitate more rapid discovery of useful medicinally active compounds. We have provided a review of the synthesis of some of the well-known fused quinazolinone topoisomerase inhibitors along with our efforts to develop access to some of the natural product like libraries of fused quinazolinones.