First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3ß/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3ß (GSK-3ß). The synthesized compounds are highly potent GSK-3ß, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 µM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Agronomic potential of two different glass-based materials as novel inorganic slow-release iron fertilizers.

BACKGROUND: Large amounts of chemical fertilizers are still currently used to compensate the soil nutrients scarcity in order to increase and sustain crop yield with consequent rising of environmental pollution and health problems. To mitigate these environmental risks, fertilizers with slow-release behaviours have been developed. The aim of this study was to assess the agronomic potential of two different glass-based materials (by-products from the ceramic sector) as inorganic slow-release iron (Fe) fertilizers. RESULTS: The X-ray powder diffraction confirmed the presence of amorphous structure and the richness in Fe of the investigated materials. The solubility analysis highlighted the slow Fe release from the glassy network and that the maximum of the Fe release was at alkaline pH suggesting their potential use as slow-release Fe fertilizers, especially in calcareous soils. The pot and leaching experiments demonstrated that although the glass-based materials increased the amount of soil available Fe, we did not observe Fe leaching and plant toxicity. This fact would suggest their reliability to increase soil fertility without negative effects on the environment. CONCLUSION: The use of glass-based materials, specifically by-products from the ceramic sectors, as inorganic slow-release Fe fertilizers can be sustained. The tests performed at three different pH conditions testified the slow-release behaviour of the tested materials and underlined that the Fe release increases at alkaline environment. Therefore, the present study pointed out the glass-based materials by products from the ceramic sector as novel slow-release and environmental-friendly fertilizers in agriculture. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Monocyclic ß-lactams loaded on hydroxyapatite: new biomaterials with enhanced antibacterial activity against resistant strains.

The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted ß-lactams. To this aim, a series of non-polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined ß-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4-acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity.

New ß-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins.

A novel series of ß-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing αvß3, αvß5, αvß6, α5ß1, αIIbß3, α4ß1, and αLß2 integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by αvß3, αvß5, α5ß1, or α4ß1 integrin, and antagonists for the integrins αvß3 and α5ß1, as well as α4ß1 and αLß2, preventing the effects elicited by the respective endogenous agonists.

Laccase-mediator system for alcohol oxidation to carbonyls or carboxylic acids: toward a sustainable synthesis of profens.

By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.

Targeting integrins αvß3 and α5ß1 with new ß-lactam derivatives.

The αvß3 and α5ß1 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new ß-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells; in particular 1, expressed a higher affinity towards α5ß1 integrin (EC50 of 12 nM) and 2 was more selective for integrin αvß3 (EC50 of 11 nM).

Azetidinone-retinoid hybrids: synthesis and differentiative effects.

As a part of a systematic investigation on the synthesis and biological activities of new ß-lactam compounds, we examined ß-lactam candidates 1, 2E and 2Z and their ability to induce cell proliferation or differentiation. Azetidinone 1 was chosen for its activity (previously evaluated) as selective HDAC8 inhibitor, whereas ß-lactams 2E and 2Z were designed to have a hybrid retinoid-azetidinone structure, de novo synthesized and fully characterized. Biological activities were determined in cellular assays on neuroblastoma cells SH-SY5Y. Azetidinone 1, 2E and 2Z led to a moderate effect in decreasing SH-SY5Y cell proliferation and ß-lactams 2E and 2Z induced an early stage differentiation. The present results uncovered a new role of specifically designed ß-lactam compounds in epigenetic regulation.

Monocyclic ß-lactams as antibacterial agents: facing antioxidant activity of N-methylthio-azetidinones.

A series of N-methylthio-ß-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the ß-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.