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.

Dihydrophenanthrene Dimers: Why and Where It Is Possible to Isolate Their Precursors.

An interesting class of compounds of natural origin is dihydrophenanthrene dimers, which are characterized by a series of remarkable biological properties. Considering the hypothesis that each dimer is obtained through a biosynthetic mechanism that involves the coupling of the corresponding radicals of the single dihydrophenanthrene unit, we identified 29 dihydrophenanthrenes. Of these dihydrophenanthrenes, 11 were new compounds that could be isolated from 10 different plant species; 11 had already been identified, but not yet isolated in the 17 different plant species from which the corresponding dimers had been isolated; and 7 were known and had been isolated in the same plant sources of the corresponding dimers. A targeted analysis of several natural extracts from specific plant sources would allow the identification of known or new molecules with potential and/or specific biological activities and, in a final analysis, would confirm the relative biosynthetic mechanism.

Silybins are stereospecific regulators of the 20S proteasome.

A reduced proteasome activity tiles excessive amyloid growth during the progress of protein conformational diseases (PCDs). Hence, the development of safe and effective proteasome enhancers represents an attractive target for the therapeutic treatment of these chronic disorders. Here we analyze two natural diastereoisomers belonging to the family of flavonolignans, Sil A and Sil B, by evaluating their capacity to increase proteasome activity. Enzyme assays carried out on yeast 20S (y20S) proteasome and in parallel on a permanently "open gate" mutant (α3ΔN) evidenced that Sil B is a more efficient 20S activator than Sil A. Conversely, in the case of human 20S proteasome (h20S) a higher affinity and more efficient activation is observed for Sil A. Driven by experimental data, computational studies further demonstrated that the taxifolin group of both diastereoisomers plays a crucial role in their anchoring to the α5/α6 groove of the outer α-ring. However, due to the different stereochemistry at C-7" and C-8" of ring D, only Sil A was able to reproduce the interactions responsible for h20S proteasome activation induced by their cognate regulatory particles. The provided silybins/h20S interaction models allowed us to rationalize their different ability to activate the peptidase activities of h20S and y20S. Our results provide structural details concerning the important role played by stereospecific interactions in driving Sil A and Sil B binding to the 20S proteasome and may support future rational design of proteasome enhancers.

Known or Never before Identified Phenanthrenes: Where It Is Possible to Isolate Them and Why.

The secondary metabolites of plant origin belong to different and numerous classes of organic compounds. One of these is that of dimeric phenanthrenes, symmetrical or not, characterized by a series of interesting biological activities. Of these compounds, 37 have been isolated since 1988, from only five plant families. Considering each dimer comprises two phenanthrenes and starting from the hypothesis that each dimer is obtained through a biosynthetic mechanism that involves the coupling of the corresponding radicals of the individual phenanthrene units, it is possible to identify 29 phenanthrenes, of which 6 not yet isolated. It is possible to establish that 16 known phenanthrenes can be isolated from 14 different plant species, just as 6 new phenanthrenes can be isolated from 6 different plant species. This would allow a targeted analysis of a few natural extracts from specific plant sources to identify known or new molecules, with potential and/or specific biological activities.

Environmental Fate of Organic Sunscreens during Water Disinfection Processes: The Formation of Degradation By-Products and Their Toxicological Profiles.

The development of any commercial product should also be aimed at reducing the risk associated with it, according to the safe-by-design concept; that is, risk assessment should always be at the center of the design, and the impact on human and environmental health should be assessed and eliminated during the product development phase and not afterwards. Unfortunately, even today, most operators in any production sector implement the philosophy of "risk management" or rather of managing the problem when it occurs, using spot interventions instead of changing the approach. This argument is also valid in the production of solar filters, which have reached a satisfactory degree of efficiency in the face of a substantial underestimation of the risks associated with their possible environmental fate. In fact, solar filters have been found in bathing waters and their environmental fate may depend on various factors such as the pH of the water, the presence of organic material, metal ions and light, and, above all, the chemical agents used in the disinfection of the water itself. Thus, during disinfection processes, the generation of dozens of products with a lower molecular weight and generally of an aromatic nature has been tested, where some of them did not receive an exact structural definition and a precise evaluation of their precise toxicological profile. Therefore, it is interesting to draw a complete picture of organic sunscreens and of the byproducts obtained under different conditions and their related ecotoxicological profile.

Octocrylene: From Sunscreens to the Degradation Pathway during Chlorination Processes: Formation of Byproducts and Their Ecotoxicity Assessment.

Octocrylene is an organic sunscreen whose main action is to absorb UVB radiation and short UVA wavelengths; it is used in various cosmetic products in order to provide an adequate sun-protection factor or to protect the cosmetic formulations themselves from UV radiation. This filter is believed to be a possible endocrine disruptor and is also questioned due to its allergic and/or photoallergic potential. However, it continues to be widely used, and it has been found in various environments, not least those of swimming pools, where it is evidently released by consumers, to the point that it is now considered an emerging micropollutant. The present investigation presents the possible chemical fate of octocrylene in the typical chlorination conditions of wastewater or swimming pools. A total of 11 disinfection byproducts were identified, and 6 were identified for the first time, and separated by HPLC. These products were identified through careful mass spectrometry studies and 1D and 2D NMR experiments. A formation mechanism has been proposed that justifies the chemical structures of all of the compounds identified. The ecotoxicological assessment of octocrylene and their products was carried out by employing Phaeodactylum tricornutum, Brachionus plicatilis and Aliivibrio fischeri as bioindicators. The ecotoxicity results reveal that toxic byproducts might be generated during the oxidation process, increasing the potential risk to the marine environment.

Phosphodiester Silybin Dimers Powerful Radical Scavengers: A Antiproliferative Activity on Different Cancer Cell Lines.

Silibinin is the main biologically active component of silymarin extract and consists of a mixture 1:1 of two diastereoisomeric flavonolignans, namely silybin A (1a) and silybin B (1b), which we call here silybins. Despite the high interest in the activity of this flavonolignan, there are still few studies that give due attention to the role of its stereochemistry and, there is still today a strong need to investigate in this area. In this regard, here we report a study concerning the radical scavenger ability and the antiproliferative activity on different cell lines, both of silybins and phosphodiester-linked silybin dimers. An efficient synthetic strategy to obtain silybin dimers in an optical pure form (6aa, 6ab and 6bb) starting from a suitable building block of silybin A and silybin B, obtained by us from natural extract silibinin, was proposed. New dimers show strong antioxidant properties, determined through hydroxyl radical (HO●) scavenging ability, comparable to the value reported for known potent antioxidants such as quercetin. A preliminary screening was performed by treating cells with 10 and 50 µM concentrations for 48 h to identify the most sensitive cell lines. The results show that silibinin compounds were active on Jurkat, A375, WM266, and HeLa, but at the tested concentrations, they did not interfere with the growth of PANC, MCF-7, HDF or U87. In particular, both monomers (1a and 1b) and dimers (6aa, 6ab and 6bb) present selective anti-proliferative activity towards leukemia cells in the mid-micromolar range and are poorly active on normal cells. They exhibit different mechanisms of action in fact all the cells treated with the 1a and 1b go completely into apoptosis, whereas only part of the cells treated with 6aa and 6ab were found to be in apoptosis.

Solid-phase synthesis of curcumin mimics and their anticancer activity against human pancreatic, prostate, and colorectal cancer cell lines.

Curcumin is a bioactive natural compound with a wide range of pharmacological properties, including antitumor activity; however, its clinical application has been limited because of its low solubility, stability, and bioavailability. In this study, a solid phase approach was proposed for the combinatorial synthesis of a mini library of the mimics of curcumin in good purity and yield. The non-effective findings in pancreatic cancer cells switched to strong growth inhibition and cell death efficacy for PC3 prostate cancer cells, and mimic 9, in which tyrosol (TYR) and homovanillyl alcohol (HVA) units were linked by a phosphodiester bond, was quite effective not only in cell growth inhibition but also in causing strong cell death under the study conditions and treatments that were not effective in PANC1 cells. The results got more exciting when we also consider the findings in SW480 human colorectal carcinoma cell line, where the growth inhibitor effects were more in line with that of the PC3 cells, but the lack of cell death effect was more in line with the PANC1 cells.

Investigation on the solid-phase synthesis of silybin prodrugs and their timed-release.

Prodrugs are ingenious derivatives of therapeutic agents designed to improve the pharmacokinetic profile of the drug. Here, we report an efficient and regioselective solid phase approach for obtaining new prodrugs of 9″-silybins conjugated with 3'-ribonucleotide units (uridine and adenosine) as pro-moieties. Uridine and adenosine conjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A and silybin B), using a NovaSyn® support functionalized with an ad hoc linker, which allowed selective detachment of only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higher than that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Our investigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even at low enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiated neuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage further investigations of uridine-silybin prodrugs as potential therapeutic agents for both oral and intravenous administration. The present synthetic approach represents a valuable strategy to the future design of new prodrugs with modified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products with strong pharmacological activities but poor bioavailability.

Secondary Effects of Hypochlorite Treatment on the Emerging Pollutant Candesartan: The Formation of Degradation Byproducts and Their Toxicological Profiles.

In recent years, many studies have reported the frequent detection of antihypertensive agents such as sartans (olmesartan, valsartan, irbesartan and candesartan) in the influents and effluents of wastewater treatment plants (WWTPs) and in the superficial waters of rivers and lakes in both Europe and North America. In this paper, the degradation pathway for candesartan (CAN) was investigated by simulating the chlorination process that is normally used to reduce microbial contamination in a WWTP. Twelve isolated degradation byproducts (DPs), four of which were isolated for the first time, were separated on a C-18 column by employing a gradient HPLC method, and their structures were identified by combining nuclear magnetic resonance and mass spectrometry and comparing the results with commercial standards. On the basis of these results, a mechanism of formation starting from the parent drug is proposed. The ecotoxicity of CAN and its DPs was studied by conducting a battery of ecotoxicity tests; bioassays were performed using Aliivibrio fischeri (bacterium), Daphnia magna (planktonic crustacean) and Raphidocelis subcapitata (alga). The ecotoxicity results shed new light on the increased toxicity of DPs compared with the parent compound.

LC and NMR Studies for Identification and Characterization of Degradation Byproducts of Olmesartan Acid, Elucidation of Their Degradation Pathway and Ecotoxicity Assessment.

The discovery of various sartans, which are among the most used antihypertensive drugs in the world, is increasingly frequent not only in wastewater but also in surface water and, in some cases, even in drinking or groundwater. In this paper, the degradation pathway of olmesartan acid, one of the most used sartans, was investigated by simulating the chlorination process normally used in a wastewater treatment plant to reduce similar emerging pollutants. The structures of nine isolated degradation byproducts (DPs), eight of which were isolated for the first time, were separated via chromatography column and HPLC methods, identified by combining nuclear magnetic resonance and mass spectrometry, and justified by a proposed mechanism of formation beginning from the parent drug. Ecotoxicity tests on olmesartan acid and its nine DPs showed that 50% of the investigated byproducts inhibited the target species Aliivibrio fischeri and Raphidocelis subcapitata, causing functional decreases of 18% and 53%, respectively.

Synthesis of new riboflavin modified ODNs: Effect of riboflavin moiety on the G-quadruplex arrangement and stability.

In the panorama of modified G-quadruplexes (G4s) with interesting proprieties, here, it has been reported the synthesis of new modified d(TGGGAG) sequences forming G-quadruplexes, with the insertion of a riboflavin unit (Rf, vitamin B2). Exploiting the flavin similarity with the hydrogen bond pattern of guanine and aiming at mimic a typical nucleoside scaffold, the synthesis of the riboflavin building block 3 it has been efficiently carried out. The effect of insertion of riboflavin mimic nucleoside on the G-quadruplex properties has been here, for the first time investigated. A biophysical characterization of Rf-modified sequences (A-D) has been carried out by circular dichroism (CD), fluorescence spectroscopy, differential scanning calorimetry (DSC) and native gel electrophoresis. CD and electrophoresis data have suggested that Rf-modified sequences are able to form parallel tetramolecular G4 structures similar to that of the unmodified sequence. Analysis of the DSC thermograms has revealed that all modified G-quadruplexes have a higher thermal stability compared with the natural sequence, particularly the stabilisation is higher when the Rf residue is introduced at the 3'-end. Further, DSC analysis has revealed that the Rf residues introduced at the 3'-end are able to form additional stabilising interactions, energetically almost comparable to the enthalpic contribution of a G-tetrad. Fluorescence measurement are consistent with this result showing that the Rf residues introduced at 3'-end are able to form stacking interactions with the adjacent bases within the G-quadruplex structure. The whole of data suggested that the introduction of Rf unit can stabilize G-quadruplex structures and can be a promising candidate for future theranostic applications.

Hotoda's Sequence and Anti-HIV Activity: Where Are We Now?

The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. In this review, we have reported the history of a strong anti-HIV agent: the 6-mer d(TGGGAG) sequence, commonly called "Hotoda's sequence". In particular, all findings reported on this sequence and its modified sequences have been discussed considering the following research phases: (i) discovery of the first 5'-modified active d(TGGGAG) sequences; (ii) synthesis of a variety of end-modified d(TGGGAG) sequences; (iii) biophysical and NMR investigations of natural and modified Hotoda's sequences; (iv); kinetic studies on the most active 5'-modified d(TGGGAG) sequences; and (v) extensive anti-HIV screening of G-quadruplexes formed by d(TGGGAG) sequences. This review aims to clarify all results obtained over the years on Hotoda's sequence, revealing its potentiality as a strong anti-HIV agent (EC50 = 14 nM).

Disinfection by-Products and Ecotoxic Risk Associated with Hypochlorite Treatment of Tramadol.

In recent years, many studies have highlighted the consistent finding of tramadol (TRA) in the effluents from wastewater treatment plants (WTPs) and also in some rivers and lakes in both Europe and North America, suggesting that TRA is removed by no more than 36% by specific disinfection treatments. The extensive use of this drug has led to environmental pollution of both water and soil, up to its detection in growing plants. In order to expand the knowledge about TRA toxicity as well as the nature of its disinfection by-products (DBPs), a simulation of the waste treatment chlorination step has been reported herein. In particular, we found seven new by-products, that together with TRA, have been assayed on different living organisms (Aliivibrio fischeri, Raphidocelis subcapitata and Daphnia magna), to test their acute and chronic toxicity. The results reported that TRA may be classified as a harmful compound to some aquatic organisms whereas its chlorinated product mixture showed no effects on any of the organisms tested. All data suggest however that TRA chlorination treatment produces a variety of DBPs which can be more harmful than TRA and a risk for the aquatic environment and human health.

Silibinin phosphodiester glyco-conjugates: Synthesis, redox behaviour and biological investigations.

New silibinin phosphodiester glyco-conjugates were synthesized by efficient phosphoramidite chemistry and were fully characterized by 2D-NMR. A wide-ranging study focused on the determination of their pKa and E° values as well as on their radical scavenging activities by different assays (DPPH, ABTS+ and HRSA) was conducted. The new glyco-conjugates are more water-soluble than silibinin, and their radical scavenging activities are higher than those of silibinin. The conjugation therefore improves both the water solubilities and antioxidant activities of the flavonolignan moieties. The serum stability was evaluated under physiological conditions, and the glyco-conjugates degraded with half-lives of 40-70 h, making them useful in pro-drug approaches. We started by treating androgen-dependent prostate cancer (PCa) LNCaP cells and then expanded our studies to androgen-independent PCa PC3 and DU145 cells. In most cases, the new derivatives significantly reduced both total and live cell numbers, albeit at different levels. Anti-HIV activities were evaluated and the glucosamine-phosphate silibinin derivative showed higher activity (IC50 = 73 µM) than silibinin.

A New Class of Synthetic Flavonolignan-Like Dimers: Still Few Molecules, but with Attractive Properties.

In recent years, there has been increasing interest in dimeric molecules due to reports of their promising therapeutic value in the treatment of numerous diseases (such as cancer, HIV, Alzheimer's and, malaria). Many reports in the literature have highlighted the ability of these molecules to interact not only with specific biologic receptors but also to induce a biological response that more than doubles the results of the corresponding monomeric counterpart. In this regard, flavonolignan dimers or simply bi-flavonolignans are an emerging class of dimeric compounds that unlike bi-flavonoids, which are very widespread in nature, consist of synthetic dimers of some flavonolignans isolated from the milk thistle Silybum marianum [L. Gaertn. (Asteraceae)]. This mini-review will discuss recent developments in the synthesis, characterization and antioxidant activity of new families of flavonolignan dimers, in light of emerging medicinal chemistry strategies.

Traditional uses, chemical composition and biological activities of Sideritis raeseri Boiss. & Heldr.

Sideritis species have been used in folk medicine for their antimicrobial, antiulcerogenic, digestive and anti-inflammatory properties. Over the years, the phytochemistry of the genus Sideritis has been studied, and various terpenoids, sterols, coumarins and especially flavonoid aglycones and glycosides have been identified. In particular, species from the Balkan Peninsula have been studied and were found to be rich in flavonoids, with valuable antioxidant activity. In the folk medicine of the Balkan countries, Sideritis raeseri is used as a herbal tea in the treatment of inflammation, gastrointestinal disorders and coughs, and also as a tonic, whereas extracts are used as a component of dietary supplements for anaemia. Its dried inflorescences are used to prepare a beverage called 'mountain tea'. In light of the considerable interest generated in the chemistry, pharmacological properties and commercial value of S. raeseri Boiss. & Heldr., we review and summarise the available literature on these plants. The review details the chemical composition of the essential oil, its mineral and polyphenol contents, the naming of these plants and their physicochemical characterisation, and the nuclear magnetic resonance spectral data and biological properties associated with the plant extracts, with a focus on their potential chemotherapeutic applications. © 2016 Society of Chemical Industry.

Chemical and organoleptic characteristics of tomato purée enriched with lyophilized tomato pomace.

BACKGROUND: Epidemiological studies have proved that tomato consumption is associated with a lower risk of developing several diseases (for example, certain types of cancers, cardiovascular diseases, macular degeneration, age-related eye disease). Many micronutrients and bioactive compounds are mainly present in peel and seeds and are lost during the processing into sauce, purée, paste and juice. RESULTS: The addition of lyophilized and powdered tomato pomace enhances the properties of purée. In this paper we report the chemical and physicochemical characterization of a purée enriched with 2% dry pomace. Comparison of the analytical data of starting purée with the enriched purée showed a significant increase of all micronutrients, without the taste and appearance being compromised or altered negatively. CONCLUSION: The product obtained is an example of a functional food rich in health-promoting phytochemicals, with the significant aspect of recovering a waste fraction of the tomato processing that would normally be disposed of in landfill, with associated costs and environmental impact.

1',5'-Anhydro-L-ribo-hexitol Adenine Nucleic Acids (α-L-HNA-A): Synthesis and Chiral Selection Properties in the Mirror Image World.

The synthesis and a preliminary investigation of the base pairing properties of (6' → 4')-linked 1',5'-anhydro-L-ribo-hexitol nucleic acids (α-L-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the "all equatorial" pyranyl sugar backbone, α-L-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-L-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids.