Emily Borretto

Microwave-assisted synthesis of N-heterocycles in medicinal chemistry

The syntheses of almost all N-heterocycles have now been successfully performed under microwave irradiation and have provided significant improvements in the reaction time and efficiency. The peculiar properties of dielectric heating give it the ability to strongly promote cyclocondensation, cycloaddition and selective N-heterocycle functionalisation and it has, therefore, very much caught the attention of the medicinal chemistry community. In this work, we present an overview of recent literature and technical advances in this research field with the aim of providing insight into the applications of microwave-assisted synthesis in the preparation of the main drug categories that contain N-heterocycle scaffolds.

Synthesis and Biological Evaluation of the First Example of NO- Donor Histone Deacetylase Inhibitor

The NO-donor histone deacetylase inhibitor 2, formally obtained by joining Entinostat 1, a moderately selective Class I histone deacetylases (HDACs) inhibitor, to a 4-(methylaminomethyl)furoxan-3-carbonitrile scaffold, is described and its preliminary biological profile discussed. This hybrid regulates Classes I and II HDACs. Nitric oxide (NO) released by the compound activates soluble guanylate cyclase (sGC), causing Class II nuclear shuttling and chromatin modifications, with consequences on gene expression. The hybrid affects a number of micro-RNAs not modulated by its individual components; it promotes myogenic differentiation, inducing the formation of larger myotubes with significantly more nuclei per fiber, in a more efficient manner than the 1:1 mixture of its two components. The hybrid is an example of a new class of NO-donor HDACs now being developed, which should be of interest for treating a number of diseases.

New Nitric Oxide or Hydrogen Sulfide Releasing Aspirins

A new series of (((R-oxy)carbonyl)oxy)methyl esters of aspirin (ASA), bearing nitric oxide (NO) or hydrogen sulfide (H(2)S) releasing groups, was synthesized, and the compounds were evaluated as new ASA co-drugs. All the products were quite stable in buffered solution at pH 1 and 7.4. Conversely, they were all rapidly metabolized, producing ASA and the NO/H(2)S releasing moiety used for their preparation. Consequent on ASA release, the compounds were capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma (PRP). The simple NO/H(2)S donor substructures were able to relax contracted rat aorta strips, with a NO- and H(2)S-dependent mechanism, respectively, but they either did not trigger antiaggregatory activity or displayed antiplatelet potency markedly below that of the related co-drug. The new products might provide a safer and improved alternative to the use of ASA principally in its anti-inflammatory and antithrombotic applications.

Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.

Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure-activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.

Effects of Ultrasound and Microwaves on Selective Reduction: Catalyst Preparation and Reactions

The reduction of organic compounds through catalytic hydrogenation is an important transformation in organic chemistry, especially in the synthesis of fine chemicals, natural products, and pharmaceuticals. This review mainly focuses on the selective reduction of substrates with multiple functional groups. Literature from the last two decades has proved the pivotal role that ultrasound and microwaves can play not only in the preparation of environmentally friendly, efficient catalysts but also in their use in catalytic reactions. Owing to the specific selective activation of the solid catalyst surface, dielectric heating and acoustic cavitation may dramatically enhance the reaction rate and selectivity. A thorough literature survey was the first step in the MAPSYN project (EU 7th Framework Program) and has the goal of the industrial demonstration of selective hydrogenations intensified by microwaves and ultrasound. Both techniques are irreplaceable tools in heterogeneous catalysis and can be expected to bring even greater success in the near future as processes are scaled up with suitable flow reactors equipped with on‐line analytical monitoring.

Ultrasound‐ and Microwave‐Assisted Preparation of Lead‐Free Palladium Catalysts: Effects on the Kinetics of Diphenylacetylene Semi‐Hydrogenation

The effect of environmentally benign enabling technologies such as ultrasound and microwaves on the preparation of the lead‐free Pd catalyst has been studied. A one‐pot method of the catalyst preparation using ultrasound‐assisted dispersion of palladium acetate in the presence of the surfactant/capping agent and boehmite support produced the catalyst containing Pd nanoparticles and reduced the number of pores larger than 4 nm in the boehmite support. This catalyst demonstrated higher activity and selectivity. The comparison of kinetic parameters for diphenylacetylene hydrogenation showed that the catalyst obtained by using the one‐pot method was seven times as active as a commercial Lindlar catalyst and selectivity towards Z‐stilbene was high. Our work also illustrated that highly selective Pd/boehmite catalysts can be prepared through ultrasound‐assisted dispersion and microwave‐assisted reduction in water under hydrogen pressure without any surfactant.

Design and synthesis of N‐benzoyl amino acid derivatives as DNA methylation inhibitors

The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N‐benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT‐dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure–activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L‐glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration‐dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.

Thymopentin down-regulates both activity and expression of iNOS in blood cells of Sézary syndrome patients

While thymopentin has been used for many years in the experimental treatment of Sézary syndrome (SS), a rare and very aggressive lymphoma, its mechanism of action is still not known. Herein we show that this peptide acts as an inhibitor of isolated iNOS and nNOS isoforms, and reduces iNOS protein/mRNA levels and iNOS activity in blood cells obtained from both healthy donors and SS patients. Similar results were obtained with TPN-2, the N(ω)-nitro analogue of the Arg-Lys motif present in thymopentin. Additional investigations are necessary to confirm the role and the relative importance of the two mechanisms of iNOS down-regulation in the therapeutic action of these peptides against SS.

Structural and biological characterization of new hybrid drugs joining an HDAC inhibitor to different NO-donors

HDAC inhibitors and NO donors have already revealed independently their broad therapeutic potential in pathologic contexts. Here we further investigated the power of their combination in a single hybrid molecule. Nitrooxy groups or substituted furoxan derivatives were joined to the α-position of the pyridine ring of the selective class I HDAC inhibitor MS-275. Biochemical analysis showed that the association with the dinitrooxy compound 31 or the furoxan derivative 16 gives hybrid compounds the ability to preserve the single moiety activities. The two new hybrid molecules were then tested in a muscle differentiation assay. The hybrid compound bearing the moiety 31 promoted the formation of large myotubes characterized by highly multinucleated fibers, possibly due to a stimulation of myoblast fusion, as implicated by the strong induction of myomaker expression. Thanks to their unique biological features, these compounds may represent new therapeutic tools for cardiovascular, neuromuscular and inflammatory diseases.