Pericyclic Reaction for Antivirals

The synthesis of new nucleoside analogues is a new approach in viral chemotherapy showing a remarkable activity towards different types of viruses. The aim of this work is to synthetize new carbocyclic nucleosides by taking advantage of the chemistry of nitrosocarbonyl intermediates and nitrile oxides. The thesis can be divided in three main topics: a) First of all, were conducted synthetic studies of nucleoside analogues of racemic 4-hydroxy-2-cyclopentenone, a scaffold often found in natural products and biologically active compounds. This core can be easily functionalized with suitable leaving groups to perform nucleophilic substitution reaction or metal-catalyzed synthesis to access nucleoside analogues by insertion of several heterobases. The reaction can be also evaluated in its optically pure version. Docking studies guided the choice of the functional groups in order to increase or modify properly the biological activity. Apoptotic activities were evaluated for the most promising compounds. b) In this part, nitrosocarbonyls were generated using a photochemical reaction method. The starting material, an hydroxamic acid or its corresponding salt, was tested in oxidant room of TBADT. The tetrabutylammonium decatungstate (TBADT) is an efficient and robust photocatalyst able to promote photoredox reactions, as well as hydrogen atom transfer processes, starting from different classes of organic substrates. The [4+2] cycloaddition of dienes with nitrosocompounds, namely the nitroso-Diels-Alder (NDA) reaction, is a versatile method to generate highly reactive acylnitroso species from hydroxamic acid derivatives. Since nitrosocarbonyl intermediates participate in a variety of organic reactions, the in situ formation of this highly reactive species using photoredox conditions furnished a general procedure for patterning surfaces bearing a range of properties. c) Finally, we proposed a new synthesis of Panobinostat, a complex hydroxamic acid with important biological properties. Specifically, it is an orally administered drug for the treatment of patients with multiple myeloma. In this context, for its relevant pharmacological role, is essential to identify new step-economy and waste-economy approach to access this important compound.

Questa tesi di dottorato ha lo scopo di sintetizzare nuovi nucleosidi carbonilici sfruttando la chimica degli intermedi nitrosocarbonilici e dei nitrilossidi. La tesi può essere suddivisa in tre argomenti principali: a) I primi studi sono stati condotti sugli analoghi nucleosidici del 4-idrossi-2-ciclopentenone, uno scaffold presente in numerosi prodotti naturali e biologicamente attivi. Questo può essere facilmente funzionalizzato utilizzando opportuni gruppi uscenti al fine di realizzare una sostituzione nucleofila per linserimento di diverse eterobasi. b) La seconda parte è dedicata alla generazione di intermedi nitrosocarbonilici usando un approccio fotochimico. Lo starting material, un acido idrossamico o un suo sale, viene ossidato per mezzo del TBADT. Questi intermedi nitrosocarbonilici possono essere poi intercettati da opportuni dieni in una cicloaddizione [4 + 2] nota come nitroso-Diels-Alder (NDA) per generare una varietà di cicloaddotti. c) Infine, lo studio e la sintesi di diversi acidi idrossamici per la generazione degli intermedi nitrosocarbonili ci ha condotti ad una nuova sintesi step-economy del Panobinostat. Il Panobinostat o commercialmente chiamato Farydak, è un acido idrossamico complesso con importanti proprietà biologiche e chemioterapiche.