Selectivity of biomolecular recognition processes: synthesis and pharmacological activity of novel biomimetic agents.

Biomimetic agents are synthetic compounds devised to resemble structures and properties of natural biomolecules with the aim to solve complex human problems. Glycomimetics, nucleoside analogues (NAs) and modified oligonucleotides (MOs) represent biomimetic agents that have found various pharmacological applications and constitute the topic of the three main sections in which this PhD thesis has been organized. The design, the synthesis and then the biological evaluation of such molecules have been undertaken; in all cases the aim was the development of new agents with targeted pharmacological activity or improved biological selectivity in several medicinal chemistry contexts

COVID-19 and pneumonia: a role for the uPA/uPAR system

Here, we highlight recent findings on the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system that suggest its potential role as a main orchestrator of fatal progression to pulmonary, kidney, and heart failure in patients with coronavirus. Patients with prolonged background inflammation can present aberrant inflammatory reactions, well recognized as the main factors that can result in death and probably sustained by a dysregulated uPA/uPAR system. SuPAR, the soluble form of uPAR, represents a biomarker of disease progression, and its levels correlate well with comorbidities associated with the death of patients with coronavirus. New drugs that regulate the uPA/uPAR system could help treat the severe complications of highly pathogenic human coronaviruses (hCoVs), including pandemic coronavirus 2019 (COVID-19)

SELECTIVITY OF BIOMOLECULAR RECOGNITION PROCESSES: SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF NOVEL BIOMIMETIC AGENTS

Biomimetic agents are synthetic compounds devised to resemble structures and properties of natural biomolecules with the aim to solve complex human problems. Glycomimetics, nucleoside analogues (NAs) and modified oligonucleotides (MOs) represent biomimetic agents that have found various pharmacological applications and constitute the topic of the three main sections in which this PhD thesis has been organized. The design, the synthesis and then the biological evaluation of such molecules have been undertaken; in all cases the aim was the development of new agents with targeted pharmacological activity or improved biological selectivity in several medicinal chemistry contexts

Synthesis of piperidine nucleosides as conformationally restricted immucillin mimics

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive con-formation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation

De novo synthesis of L-DNJ and its N-alkylated derivatives

herein we report a synthetic procedure for the preparation of L-DNJ and its N-alkylated derivatives (FIGURE 1). The highly stereocontrolled access to the iminosugar core has been devised through de novo synthesis starting from the synthetically available homologating agent ,and the Garner aldehyde . In addition, the use of polymer-bound triphenylphosphine/iodine has been conceived for the assembly of the alkyl chains, thereby providing a variety of N-alkyl L-DNJ derivatives. Biological assays for some of these derivatives are also presented, revealing an interesting therapeutic potential in the treatment of some genetic disorders including Pompe disease and Cystic Fibrosi

Highly Stereocontrolled De Novo Synthesis of N-Alkyl L-Deoxynojirimycin Derivatives and their Pharmacological Applications In Rare Diseases

Over the years, the interest for the synthesis and pharmacological behavior of iminosugars, sugar analogues in which the endocyclic oxygen of carbohydrate is replaced by an imino function, has greatly grown up. Despite their wide therapeutic potential, iminosugars and their N-alkylated congeners suffer of poor in vivo selectivity1 hampering their long-term medical applications. On the other hand, L-iminosugars have displayed in several contexts more efficient pharmacological properties than their D-antipodes toward specific enzymes, acting either as inhibitors or activators.2 Inspired by these observations, we have first tuned up a synthetic strategy to prepare enantiomerically pure L-DNJ3, i.e. L-deoxynojirimycin (to the best of our knowledge never reported before) and then we have developed an alternative route to the existing methods for N-alkylation of iminosugars and alkyl chains assembly. Particularly, L-DNJ was prepared by a stereocontrolled de novo method4 starting by the synthetically available enol thioether 1 and the Garner aldehyde

Selective Oxidation of Halophenols Catalyzed by an Artificial Miniaturized Peroxidase

The development of artificial enzymes for application in sustainable technologies, such as the transformation of environmental pollutants or biomass, is one of the most challenging goals in metalloenzyme design. In this work, we describe the oxidation of mono-, di-, tri- and penta-halogenated phenols catalyzed by the artificial metalloenzyme Fe-MC6*a. It promoted the dehalogenation of 4-fluorophenol into the corresponding 1,4-benzoquinone, while under the same experimental conditions, 4-chloro, 4-bromo and 4-iodophenol were selectively converted into higher molecular weight compounds. Analysis of the 4-chlorophenol oxidation products clarified that oligomers based on C-O bonds were exclusively formed in this case. All results show that Fe-MC6*a holds intriguing enzymatic properties, as it catalyzes halophenol oxidation with substrate-dependent chemoselectivity

Stereoconvergent Synthesis of Cyclopentenyl Nucleosides by Palladium‐Assisted Allylic Reaction

Stoichiometric Tsuji-Trost reaction of cyclopentenyl carbonates proceeds in stereoconvergent manner, selectively leading to cis configured nucleosides, regardless the relative configuration (cis or trans) of the starting substrates. As indicated by DFT calculations, the reaction outcome relies on the low activation energy related to the crucial, Pd-dependent π-inversion step. This approach may represent a useful strategy for the synthesis of bioactive carbocyclic nucleosides

New O-Glycosidation Methods for the Synthesis of Unnatural Oligosaccharides” XLII

an efficient de novo route enabling all eight L-hexoses synthesis has been developed by Guaragna et al. [3,4] based on the synthesis of the key intermediates 3 and 4 starting from the homologating agent 1. Based on capability of these sulfur-containing moieties to activate neighboring acetal functions, [5] as proved by the equilibrium existing between 3 and 4 (FIGURE 2), [6] their unprecedented activation, respectively at C1 and C4 positions, has been herein exploited to make them glycosyl donors into O-glycosidation reactions for the synthesis of di- and oligosaccharides structures containing enantiopure L-hexoses under extremely mild acidic conditions and without the need to install leaving group at the anomeric positions