Dottorato in SCIENZE FARMACEUTICHE

Titolo della tesi: Artificial macrocyclic receptors and natural products: from surface modification to total synthesis

PART A: One of the main problems in the development of immunosensors is to overcome the complexity of binding antibodies (Abs) onto the sensor surface, thus leading to a loss of sensitivity. In the last twenty years, preorganized macrocycles, i.e., calixarenes, were employed for the site-directed immobilization of Abs to promote the correct end-on orientation. Recently, due to their configuration and unique molecular recognition properties, resorcinol-based cyclooligomers, namely resorcarenes, turned out to be a good option for the construction of highly sensitive immunosensors. In this project, resorc[4]arene architectures decorated with eight methoxy groups at the upper rim and substituted at the lower rim with different functional groups (i.e., 3-bromopropyloxy and 3-azidopropiloxy substituents) were rationally designed and synthesized to tailor their recognition properties towards the Fc portion of Abs and to covalently install the artificial linkers on the multi-walled carbon nanotubes (MWCNTs) surface. Different chemical methods including nucleophilic substitution, click chemistry, or direct cycloaddition via nitrene were exploited. The MWCNTs modified with the resorc[4]arenes were morphologically and electronically characterized by field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), and X-ray photoemission spectroscopy (XPS) before the fabrication of modified electrodes. The latter were electrochemically characterized, and IgG Abs for the SARS-CoV-2 spike protein S1 (SPS1) were immobilized on their surface. The well-designed resorc[4]arene-functionalized MWCNTs-based immunosensors emerged as powerful systems for the development of more efficient immunosensing devices. PART B: Polyketides are a class of acetate derived natural compounds exhibiting a wide range of functional and structural diversities. These natural products can be isolated from diverse microorganisms and they show antimicrobic, anticancer, antifungal, antiparasitic and immunosuppressive properties. In the past few years, an attempt to isolate natural compounds from myxobacteria allowed to isolate pentacaronic acid (Figure 1) from Sorangium cellulosum. This polyketide has a 24 carbon atoms skeleton featuring 6 E-configured double bonds and 7 stereocenters, 5 of which are contiguous, delimiting a five-membered ring. The absolute configurations of each stereocenter have been defined except for the one in C4, which is assumed to be S-configured, due to the structural similarity between pentacaronic acid and maltepolide E. The synthetic strategy to pentacaronic acid relies on the coupling of 3 major chiral fragments: the eastern fragment can be connected by a Nozaki-Hiyama-Takai-Kishi reaction whereas the eastern fragment can be attached by exploiting a Heck coupling. The eastern fragment, containing the five-membered ring can be prepared by a SOMO-activated radical cyclization reaction catalyzed by an Ir (III)-photocatalyst, whereas the rest of the stereochemistry of the fragment is built up by an Oppolzer aldol reaction.