Progettazione e sintesi stereoselettiva di composti attivi verso bersagli proteici coinvolti in patologie virali e tumorali

The research program of UO MI is part of the national project involving several research groups with different expertise, which are working yogether to identify new molecules active in specific biological target. The expertise of UO MI allow to develop side by side compounds for the activity towards viral and cellular targets, working through different biological mechanisms as follows: a) active as anticancer compounds through inhibition of topoisomerase I b) active as anticancer compounds through inhibition of the mitotic spindle c) active as antiviral compounds inhibitors of glycosidase For topoisomerase I inhibitors the project consists of the synthesis of tetra- and pentacyclic systems, containing the pyrrolo[3,2-de]acridine skeleton bearing various substituents with different polarity and correlated, based on molecular modelling studies, to the class of amptothecins. A sequential type of reaction aimed at obtaining heteropolycyclic systems involves the use of Pd-catalyzed N-arylation and acylation reactions. Starting from tryptamine, the synthetic pathway will avail itself also of environmentally friendly methods such as solvent-free reactions, the use of very low catalyst loading (below 0.1%) and the use of non-conventional heating (microwave), then with short reaction times. The molecules studied as inhibitors of tubulin polymerization are hexahydrobenzophenantridine, having different substituents and stereochemistry, structurally correlated to the class of chelidonine alkaloids. It will be developed a new synthetic protocol that requires few steps but which involves control of both the diastereo- and the enantioselection, using as substrate 2,3-diaryl-beta-aminoacids in their turn obtained by diastereoselective methods. The synthesis of the heteropolycyclic systems of interest can be efficiently achieved by using sequential reactions which also require the use of transition metal catalysis, a field in which the UO has extensive experience. The glycosidase inhibitors identified are active toward the viral neuraminidase enzyme, a glycosidase that catalyzes the hydrolysis of neuraminic acid. The compounds under study are polyfunctionalized cyclopentanes, having as reference Peramivir molecule particularly active in the treatment of influenza H1N1. This molecule, however, has the disadvantage of being poorly bioavailable and for this reason the study of analogues orally administrable is a topical research field . The stereoselective synthesis of the cyclopentane skeleton will have as key point the functionalization of a dihydroisoxazole ring arising from a bicyclic or tricyclic system obtained by 1,3-dipolar.