Synthesis of derivatives of monosaccharides for drug discovery”

Abstract

Owing to the broad abundance in nature and the unique stereochemical and functional characteristics associated, carbohydrates are an extremely important class of compounds. There are many pharmaceutical products containing carbohydrates or modified carbohydrates as therapeutic agents, such as, Streptomycin, Gentamycin, Neomycin, Kanamycin etc containing amino sugars, which have established themselves as potential antibiotics. Synthetic carbohydrates used as drugs are few in number. The nitrate ester of isosorbide, isosorbide-5-nitrate and isosorbide dinitrate are used in acute anginal attack treatment. Some of the bioactive compounds derived from carbohydrates have been used as drug e.g. Acarbose, Voglibose, Miglitol for diabetes, AZT for AIDS/HIV infection, Topiramate for epilepsy, Acyclovir and other nucleoside analogs for Antiviral chemotherapy etc. Carbohydrate metal complex are used in the treatment of rheumatoid arthritis e.g. auranofin, aurothioglucose. Apart from the carbohydrate based synthetic therapeutics, various naturally occurring carbohydrate structures have shown significant biological activity, for example, glycosylated saponins and flavonoid glycosides. However, isolation of these bioactive molecules from natural sources is not an easy task. Therefore, chemical syntheses of these active molecules have become inevitable. In last few years carbohydrates are being increasingly used by medicinal and synthetic chemists for the development of new therapeutics. So presently there is a strong demand to develop the new methods for the synthesis of diverse carbohydrate derivatives. Among monosaccharide derived synthons, commercially available methyl α,Dglucopyranoside and methyl α,D-mannopyranoside are two important molecules that have been widely used in asymmetric synthesis. In our present study we have used methyl α,D-glucopyranoside and methyl α,D-mannopyranoside for the syntheses of stereochemically pure biologically important molecules. This study demonstrates the potential of these sugars in the area of asymmetric synthesis and drug discovery. The thesis comprises of four chapters. Chapter1 divided in to two parts. Part-A of this chapter describes a brief review on the iodocyclization of alkenic alcohols and ethers. From the literature, all the information about the iodocyclization of these unsaturated molecules are compiled at one place. Iodocyclization reaction has received significant attention in recent years towards the synthesis of natural products and molecules of biological relevance. Part-B describes the synthesis of 2,5-trans and 2,5-cis tetrasubstituted tetrahydrofurans from sugar derived alkenic alcohols by using iodocyclization reaction. Chapter 2 consists of two parts. Part-A presents a brief account on synthesis of cytotoxic natural product varitriol, its novel isomers and analogues. The biological activity of this molecule makes it an attractive target for synthetic chemists. Part-B describes first total synthesis of (+)-varitriol starting from methyl α,D-mannopyranoside by utilizing iodocyclization as the key step. Chapter 3 has also been divided into two parts. Part-A contains a brief review on literature methods towards the synthesis of gabosines and their isomers. In recent years these biological important natural products have received much interest toward their synthesis. Part-B of this chapter describes the simple and efficient synthesis of gabosine A, 4-epigabosine A and 4-epigabosine E starting from commercially available sugars. Chapter 4 deals with the diastereoselective Morita-Baylis-Hillman reaction of sugar derived cyclic enone with aromatic aldehydes in presence lewis acid as catalyst for the preparation of novel analogues of gabosines. Each chapter followed by the experimental data, selected spectra and bibliography are presented. The compound numbers, figure numbers, scheme numbers and bibliography numbers are separate for each data. The list of abbreviations is presented at the beginning of the dissertation for referring.