Diversity-Oriented Synthesis of novel glyco- and peptidomimetic scaffolds

After an impressive growth at the end of the last century, the number of new molecular entities launched on the market dramatically decreased in recent years. Thus, there is a need for efficient synthetic processes capable of generating an high number of different molecules, which differ not only for the appendages, but also for the molecular skeleton. In this context, Diversity-Oriented Synthesis (DOS) has proved to be very effective in the achievement of high quality small molecules collections for high-throughput screening and phenotypic assays and chemical genetics studies, leading to the discovery of new lead compounds. The aim of this thesis work is to apply the principles of the DOS to obtain densely functionalized molecular scaffolds, with potential glyco- and/or peptidomimetic moieties. In particular, in a first part, the synthesis of six skeletally different compounds starting from D-mannose has been discussed, together with their application in a phenotypic screening. This cell-based assay, combined with follow up synthesis and further biological studies, led to the discovery of the hexahydro-2H-furo[3,2-b][1,4]oxazine structure as an active modulator of MDA-MB-231 cell growth, through cytostatic effect. Then, the synthesis of a dipeptide isoster, the dihydropyrazinone skeleton, through morpholine acetal rearrangement has been developed. Finally, during a secondment activity of this PhD in the group of Prof. Darren J. Dixon at the University of Oxford, the generation of α-amino nitriles from tertiary amides and lactams was studied and applied in the late stage functionalization of drugs and natural products.