Synthesis, biological evaluation and metadynamics simulations of novel N-methyl ß-sheet breaker peptides as inhibitors of Alzheimer's ß-amyloid fibrillogenesis.

Several scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of ß-amyloid proteins in the brain. Because Aß is self-assembling, one possible design strategy is to inhibit the aggregation of Aß peptides using short peptide fragments homologous to the full-length wild-type Aß protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called ß-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.

Percarbonate mediated advanced oxidation of irbesartan: A suitable alternative to chlorination?

This study aims to investigate the environmental fate of irbesartan when subjected to activated percarbonate treatment. The investigation delves into the formation of disinfection byproducts (DBPs) and evaluates their toxicity, and it seeks to draw comparisons with outcomes from treatment with sodium hypochlorite, already characterized in previous findings. The proposed treatment indicates the formation of at least 11 DBPs - eight identified for the first time - which have been isolated by various chromatographic techniques, identified by Nuclear Magnetic Resonance and Mass Spectrometry studies and for which a mechanism has been proposed to elucidate their formation. To evaluate irbesartan's biological impact during treatment with sodium percarbonate (SPC), a toxicity study of the DBPs was conducted using Daphnia magna, Aliivibrio fischeri, and Raphidocelis subcapitata, three model organisms. The ecotoxicity was evaluated using the Ecological Structure-Activity Relationships (ECOSAR) computer program and compared with experimental results. Compared to chlorination treatment, a lower mineralization percentage (-43 %) and amount of DBPs at least twice higher were observed. Toxicity assessment highlighted that DBPs formed during SPC treatment were more toxic than those from chlorination. ECOSAR predicted toxicity aligned with experimental findings. Additionally, the DBPs exhibited varying levels of toxicity, primarily attributable to the presence of aromatic and hydroxyl groups in their chemical structure, indicating that SPC treatment is not suitable for treatment of irbesartan polluted waters.

Innovative Cosmeceutical Ingredients: Harnessing Selenosugar-Linked Hydroxycinnamic Acids for Antioxidant and Wound-Healing Properties.

Selenosugars are gaining growing interest due to their antioxidant efficacy, and their ability to inhibit glycosidases, repair skin tissue or reduce endothelial dysfunction. Among selenosugars, those in which selenium replaces heterocyclic oxygen in a 5-membered sugar were our focus, and their coupling with phenolic compounds appears to be a strategy aimed at producing new compounds with enhanced antioxidant efficacy. In this context, the Mitsunobu reaction has been advantageously explored to obtain trans-p-coumaroyl-1,4-deoxy-2,3-O-isopropylidene-4-seleno-d-ribose, trans-caffeoyl-1,4-deoxy-2,3-O-isopropylidene-4-seleno-d-ribose, and trans-feruloyl-1,4-deoxy-2,3-O-isopropylidene-4-seleno-d-ribose. These compounds underwent removal of the iso-propylidene group, to provide the corresponding hydroxycinnamoyl-1,4-deoxy-4-seleno-d-ribose. All compounds were characterized by Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). This latter technique was pivotal for ensuing cellular metabolomics analyses. In fact, after evaluating the anti-radical efficacy through 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) methods, which underline the massive role of the phenolic moiety in establishing efficacy, the compounds, whose cytotoxicity was first screened in two highly oxidative-stress-sensitive cells, were tested for their wound healing properties towards human HaCaT keratinocytes cells. Caffeoyl- and feruloyl selenosugars exerted a dose-dependent repair activity, while, as highlighted by the metabolomic approach, they were poorly taken up within the cells.

Tackling Losartan Contamination: The Promise of Peroxymonosulfate/Fe(II) Advanced Oxidation Processes.

Losartan, an angiotensin II receptor antagonist frequently detected in wastewater effluents, poses considerable risks to both aquatic ecosystems and human health. Seeking to address this challenge, advanced oxidation processes (AOPs) emerge as robust methodologies for the efficient elimination of such contaminants. In this study, the degradation of Losartan was investigated in the presence of activated peroxymonosulfate (PMS), leveraging ferrous iron as a catalyst to enhance the oxidation process. Utilizing advanced analytical techniques such as NMR and mass spectrometry, nine distinct byproducts were characterized. Notably, seven of these byproducts were identified for the first time, providing novel insights into the degradation pathway of Losartan. The study delved into the kinetics of the degradation process, assessing the degradation efficiency attained when employing the catalyst alone versus when using it in combination with PMS. The results revealed that Losartan degradation reached a significant level of 64%, underscoring the efficacy of PMS/Fe(II) AOP techniques as promising strategies for the removal of Losartan from water systems. This research not only enriches our understanding of pollutant degradation mechanisms, but also paves the way for the development of sustainable water treatment technologies, specifically targeting the removal of pharmaceutical contaminants from aquatic environments.

Risk assessment of natural and synthetic fibers in aquatic environment: A critical review.

Marine microplastics, categorized as primary and secondary, including synthetic microfibers like polyethylene terephthalate (PET), polypropylene (PP) and acrylic (PC), represent a potential environmental concern. The complex classification of these fibers, originating from diverse sources such as textiles and many others commercial goods, prompts a need for understanding their impact on aquatic organisms. This study assesses the ecological risks associated with both natural and synthetic fibers in aquatic ecosystems, focusing on toxicity data and their effects on taxonomic groups like Mollusca, Arthropoda, Echinodermata, Cnidaria, and Chordata. To carry out species sensitivity distribution (SSD) curves, a comprehensive analysis of scientific literature was conducted, collecting toxicity data related to various fibers. The resulting SSDs provide insights into the relative sensitivity of different taxonomic groups. The potential ecological risks were evaluated by comparing measured concentrations in diverse aquatic environments with Predicted No-Effect Concentration (PNEC) values. The calculation of Risk Quotient (RQ) allowed to indicate areas where fibers abundance poses a potential threat to aquatic organisms. The study reveals that nylon fibers can pose the highest toxicity risk, especially in Atlantic and Pacific Ocean, Arabian Gulf and VietNam river. Mollusca emerged as particularly sensitive to different fiber types, likely due to their body structure facilitating the accumulation of microfibers. The research emphasizes the urgent need for further studies to get data to human health risk analysis and to address comprehensive environmental management strategies to address the global issue of microfiber pollution.

Stereoselective Synthesis of Selenium-Containing Glycoconjugates via the Mitsunobu Reaction.

A simple and efficient route for the synthesis of new glycoconjugates has been developed. The approach acts as a model for a mini-library of compounds with a deoxy-selenosugar core joined to a polyphenolic moiety with well-known antioxidant properties. An unexpected stereocontrol detected in the Mitsunobu key reaction led to the most attractive product showing a natural d-configuration. Thus, we were able to obtain the target molecules from the commercially available d-ribose via a shorter and convenient sequence of reactions.

An 1H NMR study of the cytarabine degradation in clinical conditions to avoid drug waste, decrease therapy costs and improve patient compliance in acute leukemia.

Cytarabine, the 4-amino-1-(ß-D-arabinofuranosyl)-2(1H)-pyrimidinone, (ARA-C) is an antimetabolite cytidine analogue used worldwide as key drug in the management of leukaemia. As specified in the manufacturers' instructions, once the components-sterile water and cytarabine powder-are unpackaged and mixed, the solution begins to degrade after 6 hours at room temperature and 12 hours at 4°C. To evaluate how to avoid wasting the drug in short-term, low-dose treatment regimens, the reconstituted samples, stored at 25°C and 4°C, were analyzed every day of the test week by reversed-phase HPLC and high-field NMR spectroscopy. All the samples remained unchanged for the entire week, which corresponds to the time required to administer the entire commercial drug package during low-dose therapeutic regimens. The drug solution was stored in a glass container at 4°C in an ordinary freezer and drawn with sterile plastic syringes; during this period, no bacterial or fungal contamination was observed. Our findings show that an cytarabine solution prepared and stored in the original vials retains its efficacy and safety and can, therefore, be divided into small doses to be administered over more days, thus avoiding unnecessary expensive and harmful waste of the drug preparation. Moreover, patients who require daily administration of the drug could undergo the infusion at home without need to go to hospital. The stability of the aliquots would help decrease hospitalization costs.

Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new l-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors.

A series of l-lysine-conjugated pyridophenoxazinones 2-5 and 2'-5' were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV-vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5'-GC-3' base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIß and stimulate the formation of covalent Topo II-DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone-l-lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation.

NF-κB-Dependent Production of ROS and Restriction of HSV-1 Infection in U937 Monocytic Cells.

Herpes simplex virus 1 (HSV-1) can infect a wide range of cell types, including cells of the adaptive and innate immunity but, normally, it completes a fully-permissive replication cycle only in epithelial or neural cells. Complex mechanisms controlling this delicate balance in immune cells and consequent restriction of HSV-1 infection in these cells have not been completely elucidated. We have recently demonstrated that the transcription factor nuclear factor kappa B (NF-κB) can act as a main permissiveness regulator of HSV-1 infection in monocytic cells, however, mediators involved in this regulation have not been identified. To better define mechanisms involved in this phenomenon and, particularly, the possible involvement of ROS, wild type U937 cells or U937 cells stably transfected with a dominant-negative (DN) IκB-mutant and selenium-containing compounds, as anti-oxidants, were utilized. The main results can be summarized as follows. HSV-1 infection induces an immediate ROS production in U937 monocytic cells that can efficiently activate NF-κB but not in DN-IκB-mutant cells. Treatment with selenium-containing antioxidants efficiently inhibited HSV-1-induced ROS generation while producing increased levels of HSV-1 replication and a reduction of HSV-1-induced NF-κB activation in U937 monocytic cells. Our results suggest a scenario in which an efficient NF-κB-dependent ROS production in response to infection could contribute in limiting HSV-1 replication in monocytes/macrophages, thus avoiding possible irreparable damage to the innate immune system of the host during HSV-1 infection.

Identification of novel microsomal prostaglandin E2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening.

Identification of new microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (∼30% inhibition at 10 µM). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC50 = 4.6 ± 0.2 µM for 15; IC50 = 2.4 ± 1.0 µM for 20; IC50 = 2.4 ± 0.8 µM for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.

Se-(2-aminoalkyl)selenocysteines as biochemical redox agents. A tool to contrast cell injury induced by aflatoxin B1 in HepG2 cells.

Se-(2-aminoalkyl)selenocysteines were shown to have a chemoprotective activity towards HepG2 cells, contrasting the cell damage of aflatoxin B1. The results of this study suggest that our newly synthesized seleno-diamino acids are apparently endowed with a potent protective potential against cell damage caused by AFB1 similar to, or even higher than, that exerted by the reference compound Se-Me-SeCys. The protective effect does not seem to be absolute, i.e., merely determined by the presence of the chalcogen atom, but rather strictly related to the molecular structure of the new compounds tested. From this point of view, Se-(2-aminoalkyl)selenocysteines may represent a new class of biochemical redox agents fruitfully exploitable to contrast aflatoxin toxicity, at the same time a sound medical application and an economically relevant agricultural issue.

D-Glucosamine in a chimeric prolinamide organocatalyst for direct asymmetric aldol addition.

O-TBDPS D-glucosamine coupled with l-proline is reported to act as an efficient organocatalyst in the accomplishment of direct aldol reactions. Excellent results, in terms of chemical yields, as well as diastereomeric and enantiomeric ratios, are reported for the catalyzed additions of cyclohexanone and acetone to variously substituted benzaldehydes.

Proline-beta(3)-amino-ester dipeptides as efficient catalysts for enantioselective direct aldol reaction in aqueous medium.

Dipeptides obtained from l-proline and beta(3)-l-amino acids are reported to catalyze enantioselective direct aldol reaction in aqueous medium, leading to significant anti:syn diastereomeric ratios and enantiomeric excesses. The simple introduction of a polar substituent at the C-2 position of the beta(3)-l-amino acid was also found to enhance appreciably both diastereo- and enantioselectivity of the catalyst.

New sialyl Lewis(x) mimic containing an alpha-substituted beta(3)-amino acid spacer.

A highly convergent and efficient synthesis of a new sialyl Lewis(x) (sLe(x)) mimic, which was predicted by computational studies to fulfil the spacial requirements for a selectin antagonist, has been developed. With a beta(2,3)-amino acid residue l-galactose (bioisostere of the l-fucose moiety present in the natural sLe(x)) and succinate are linked, leading to a mimic of sLe(x) that contains all the required pharmacophores, namely the 3- and 4-hydroxy group of l-fucose, the 4- and 6-hydroxy group of d-galactose and the carboxylic acid of N-acetylneuraminic acid. The key step of the synthesis involves a tandem reaction consisting of a N-deprotection and a suitable O-->N intramolecular acyl migration reaction which is promoted by cerium ammonium nitrate (CAN). Finally, the new sialyl Lewis(x) mimic was biologically evaluated in a competitive binding assay.

A general route to D- and L-six-membered nucleoside analogues.

A simple synthetic route for novel L-(as well as D-) six-membered nucleosides is described. Particularly, we have provided a general approach to the synthesis of azasugar-based nucleosides, which preparation has been easily achieved starting from the coupling of our three carbon homologating agent 1 with the well known Garner aldehyde 4. Further suitable and stereocontrolled functionalizations of the intermediate 9 will provide, after the base insertion, a wide class of six membered modified azanucleosides to be tested as NRTIs.

A general approach to the synthesis of 1-deoxy-L-iminosugars.

A stereoselective procedure for the preparation of non-naturally occurring deoxy iminosugars belonging to L-series has been developed. The synthesis involves the construction of the key intermediate bicycle pyperidine 8, available in few steps by the coupling of the heterocyclic synthon 3 and the readily available Garner aldehyde 4.

A versatile route to L-hexoses: synthesis of L-mannose and L-altrose.

[reaction: see text] An efficient route for the synthesis of orthogonally protected l-sugars has been opened up, starting from the heterocyclic homologating agent 1 and 2,3-O-isopropylidene-l-glyceraldehyde (2). Our synthetic path enables the synthesis of a 2,3-unsaturated-l-pyranoside, which can be suitably functionalized to afford the desired l-hexoses. In this paper, we report the synthesis of l-manno- and l-altro-pyranosides. Moreover, this strategy may be used to prepare all eight sugars and their derivatives in either enantiomeric form.

Synthesis of 4-deoxy-L-(and D-)hexoses from chiral noncarbohydrate building blocks.

4-Deoxy-l-hexoses were synthesized starting from our previously reported reagent 1 and (R)-benzyl glycidyl ether, which led in few steps to a substituted dihydropyran 6. The stereocontrolled hydroxylation of the latter afforded the corresponding 4-deoxy-l-hexoses 7a, 9, and 11. The same procedure, starting from (S)-benzyl glycidyl ether, enabled the preparation of their d-series enantiomers.

A novel approach to the stereocontrolled synthesis of C-vinyl beta-D-galactopyranosides.

Reaction of a lithiated dithiinyl reagent with a O-perbenzylated D-glycono-delta-lactone readily generates the corresponding masked C-vinyl galactosides in high yields and full beta-selectivity. Removal of the sulfur mask renders the free vinyl aglycone with the vinyl group in either the Z or E configuration, depending on the desulfurization conditions chosen.