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Pseudomonas aeruginosa (PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth. Pyocyanin is one of the virulence factors whose production is modulated by the Pseudomonas quinolone signal (PQS) through its receptor PqsR. Different PqsR modulators have been synthesized over the years, highlighting this new powerful therapeutic strategy. Based on the promising structure of quinazolin-4(3H)-one, we developed compounds 7a–d, 8a,b, 9, 10, and 11a–f able to reduce biofilm formation and the production of virulence factors (pyocyanin and pyoverdine) at 50 µM in two PA strains responsible for CF acute and chronic infections. The developed compounds did not reduce the cell viability of IB3-1 bronchial CF cells, and computational studies confirmed the potential ability of novel compounds to act as potential Pqs system modulators. [ABSTRACT FROM AUTHOR]

[Display omitted] • Application of a research platform for food geographical authentication. • Multivariate investigation for Allium ampeloprasum L. from Valdichiana (Tuscany). • A. ampeloprasum L. showed a different chemical composition compared to A. sativum. • Glutathione was identified as a potential marker of authentication. • A. ampeloprasum L. extracts displayed interesting vasoactive properties. A research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.), mainly produced in southern Tuscany-(Allium ampeloprasum). The isotopic composition allowed the product to be geographically characterized. Flavonoids, like (+)-catechin, cinnamic acids, quercetin glycosides were identified. The samples showed also a significant amount of dipeptides, sulphur-containing metabolites and glutathione, the latter of which could be considered a molecular marker of the analyzed elephant garlic. For nutraceutical profiling to reach quality labels, extracts were investigated in specific biological assays, displaying interesting vasorelaxant properties in rat aorta by mediating nitric oxide release from the endothelium and exhibited positive inotropic and negative chronotropic effects in rat perfused heart. [ABSTRACT FROM AUTHOR]

Summary: An innovative functional food with symbiotic and functional potential was produced by combining probiotic milk kefir, and white grape‐seed pomace obtained by UAE (ultrasound‐assisted extraction) rich in catechin and glycosylated flavonoids. The milk kefir was fortified by adding, after 24 h of fermentation, a polymer of inulin grafted with seed extract. The inulin/grape extract‐enriched polymer showed a higher antioxidant profile (P < 0.05). Simulated in vitro digestion demonstrated that 50 g of the kefir product would result in the delivery of antioxidants equivalent to 300 mg of ascorbic acid. The integrity of the intestinal barrier functions was not compromised by kefir treatments (at 10 μg mL‐1). [ABSTRACT FROM AUTHOR]

Summary: Olive pomaces from Southern Italy autochthonous cultivars (Carolea, Nocellara and Roggianella) were eco‐friendly extracted to reach value‐added ingredients for the production of fortified pear beverages. Chemical composition of the extracts was carried out by 1H‐NMR analysis, while antioxidant features were in vitro evaluated. The extracts displayed remarkable scavenger properties against DPPH (IC50 values in the range 0.051–0.171 mg mL−1) and ABTS (IC50 values in the range 0.035–0.047 mg mL−1) radical species. Reactive species in the extracts and inulin chains were involved in an eco‐friendly radical process by grafting reaction to obtain macromolecular conjugates with outstanding antioxidant features, in terms of both antioxidant and scavenging performances, representing an attractive source in the design of functional foods. In this context, the conjugates were employed to enrich pear juice, to achieve reinforced beverages displaying remarkable antioxidant properties in comparison with its non‐functional counterparts, as well as its maintenance over time (20 days). [ABSTRACT FROM AUTHOR]

4,5-Dihydropyrrolo [1,2-a]quinoxalines are interesting druggable scaffolds, with multifaceted biological properties, including anticancer properties targeting the G protein-coupled estrogen receptor 1 (GPER). In this work, the synthesis and preliminary antiproliferative activity of a small set of new 4,5-dihydropyrrolo[1,2-a]quinoxalines (18-20) and pyrrolo[1,2-a]quinoxalines (21, 22) has been reported, inspired by known antiproliferative agents (G-1, G-15, and G-36). The synthesis of the pyrroloquinoxalinic core was employed following the Pictet–Spengler reaction, using the surfactant p-dodecylbenzene sulphonic acid (p-DBSA), as catalyst. It demonstrated efficiency in the catalysis of the 4-phenylpyrrole [1,2-a] quinoxaline type compound formation in mild solvents such as water, ethanol, and hydroalcoholic solutions. In addition, the reactions proceeded in a short time (between 15 and 120 minutes) at room temperature and with high yields. The in vitro MTT assays showed that the presence of isopropyl groups furnished promising antiproliferative compounds. Although, the acetyl group provided also antiproliferative effects, breaking down its responsibility in the GPER transactivation. Nevertheless, it is possible to conclude that the 4,5-dihydropyrrolo[1,2-a]quinoxalines remain a feasible scaffold to develop anticancer agents against GPER-expressing cells. [ABSTRACT FROM AUTHOR]

The hybrid molecule Quercetin‐3‐oleate (AV2), accommodates within the binding pocket for allosteric full GPR40 agonists. AV2 endorses skin wound healing acting as a promoter of keratinocytes proliferation and overcomes immunosuppressive conditions in vitro. AV2 stimulated HaCaT wound healing by 51% compared to the untreated control, at the concentration of 1 μM with slight TGF‐β production and MMP‐9 release. Pretreatment with the known GPR40 antagonist DC260126 abolished its wound healing power. Docking simulations suggested that both molecules share the same binding site. [ABSTRACT FROM AUTHOR]

The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1 , was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2 , was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee products, including honey. Honey has long been known for its medicinal and health promoting properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content, which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of polyphenols in honey showed antiproliferative property against several types of cancer. This review focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis, initiation, proliferation and progression, both in vitro and in vivo , as well as on its adjuvant effect in cancer therapy. Although a possible application of honey and its active compounds as drugs against cancer is still far away from clinical practice, scientific results highlight that they could be used as immune booster for patients undergoing chemotherapy. They showed protective effects against the common exasperating and disabling side effects, mostly mucositis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Artificial intelligence accelerates the drug discovery. • O -substituted morin derivatives show interesting vasorelaxant activity. • Ca V 1.2 channels seem to be the main targets involved in the vasorelaxant activity. • The pentamethyl derivative 5a reveals a multi-target activity. Morin is a vasorelaxant flavonoid, whose activity is ascribable to Ca V 1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with Ca V 1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a - c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a - c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a , the series' most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a ≈ 5c > 5b inhibited Ba2+ current through Ca V 1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of K Ca 1.1 channel currents. [ABSTRACT FROM AUTHOR]

In this study, we investigate the anti-proliferative activity of a small library of 7-substituted 5 H -pyrrolo[1,2- a ][3,1]benzoxazin-5-one derivatives, against a panel of human cancer cell lines. We reported the synthesis of these compounds in a previous work. 7-Bromo-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one showed a promising anti-proliferative effect. As starting material for Suzuki-Miyaura cross coupling reaction, it was selected for the design and the synthesis of six further derivatives, with the aim to better define structure-activity relationships. The anti-proliferative MTT assay revealed a dose-dependent reduction of cell viability, especially for 7-([1,1′-biphenyl]-4-yl)-5 H -benzo[ d ]pyrrolo[2,1- b ][1,3]oxazin-5-one. Cell cycle and western blotting analysis suggested apoptosis as possible mechanism for its anti-proliferative activity. These preliminary results encourage our interest for further optimizations. [ABSTRACT FROM AUTHOR]

Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily of redox enzymes. PDI is a multifunctional protein that catalyzes disulfide bond formation, cleavage, and rearrangement in unfolded or misfolded proteins and functions as a chaperone in the endoplasmic reticulum. Besides acting as a protein folding catalyst, several evidences have suggested that PDI can bind small molecules containing, for example, a phenolic structure, which includes the estrogenic one. Increasing studies indicate that PDI is involved in both physiology and pathophysiology of cells and tissues and is involved in the survival and proliferation of different cancers. Propionic acid carbamoyl methyl amides (PACMAs) showed anticancer activity in human ovarian cancer, both in vitro and in vivo, by inhibiting PDI. The inhibition of PDI’s activity may have a therapeutic role, in various diseases, including cancer. In the present study, we designed and synthesized a diversified small library of compounds with the aim of identifying a new class of PDI inhibitors. Most of synthesized compounds showed a good inhibitory potency against PDI and particularly 4-methyl substituted 2,6-di-tert-butylphenol derivatives (8–10) presented an antiproliferative activity in a wide panel of human cancer cell lines, including ovarian ones. [ABSTRACT FROM AUTHOR]

Fatty acids and polyphenols represent different classes of pharmacologically active molecules. Hybrid derivatives of these compounds are interesting therapeutic tools. They could be obtained using enzymatic approaches, which allow regioselective derivatizations. In this short note, the pancreatic porcine lipase was employed to mediate the regioselective synthesis of 7-docosahexaenoyl-quercetin was described. The C-7 regioisomer formation was confirmed by 1H-NMR experiment. Generally, in this approach the alcoholic OH- was preferred when present. Nevertheless, in this case, it was demonstrated that the hindrance of the acyl group is a variable to obtain a good regioselectivity in C-7 position, employing only one-step reaction. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators. [ABSTRACT FROM AUTHOR]

[Display omitted] Ca V 1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca V 1.2 and K Ca 1.1 channels, both in vitro and in silico , as well as on the contractile responses of rat aorta rings. All compounds were effective Ca V 1.2 channel blockers, positioning in the α 1C subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated K Ca 1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K Ca 1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]

• Twenty-four quercetin derivatives were designed according to the key chemically reactive centers. • A rational docking simulation was carried out to obtain the most accurate binding mode for each ligand. • Semi-synthetic hybrids were synthesized endowing substituents with known vasoactive properties. • Three hybrids bind inside the K Ca 1.1 channel binding pocket located in the S6/RCK linker. • The derivatization of quercetin in C7 and C4′ position improves its beneficial vascular activity. Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular K Ca 1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of Ca V 1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective K Ca 1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the K Ca 1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting Ca V 1.2 channel blocking activity. The lipoyl derivatives 1F and 3F , though showing pharmacological and electrophysiological features similar to those of quercetin, seemed to be more effective as K Ca 1.1 channel stimulators as compared to the parent compound. The strategy pursued demonstrated how different chemical substituents on the quercetin core can change/invert its effect on Ca V 1.2 channels or enhance its K Ca 1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids. [ABSTRACT FROM AUTHOR]

The winemaking process produces a huge number of pomaces that generally are used for energy purposes. Further valuable applications such as health-promoting properties are still under investigation. The seeds of the white berries of Mantonico and Pecorello cv. were extracted in a Soxhlet apparatus, using n-hexane and chloroform as solvents. Extracts were characterized by NMR and GC-MS analyses. They were assayed in vitro as wound healing and anti-inflammatory agents in HaCaT and RAW 264.7 cell lines, respectively. n-hexane Mantonico extract resulted in the most interesting wound healing sample, while n-hexane Pecorello, containing a good number of carotenoids, resulted in a good anti-inflammatory candidate. These preliminary findings underlined the benefit of grape seed extracts valorization due to their health-promoting properties. [ABSTRACT FROM AUTHOR]

Several epidemiological studies demonstrate that moderate (red) wine consumption may afford protection against cardiovascular diseases. Protection is ascribed to the biological activity of wine components, many of which, however, are discarded during winemaking. In vitro rat thoracic aorta rings contracted with phenylephrine or KCl were used to assess the vasorelaxant activity of extracts from wine pomaces (seeds and skins) of the Calabrian autochthonous grape variety Magliocco dolce (Arvino). NMR spectroscopy was used to ascertain their chemical composition. Data demonstrate that seed and skin, but not must, extracts are capable of relaxing vascular preparations in an endothelium-dependent manner, similarly to the red wine extract, due to the presence of comparable amounts of bioactive constituents. In rings pre-contracted with 20–30 mM KCl, only seed extracts showed a moderate relaxation. The most efficacious vasodilating extract (wine) showed a good antioxidant profile in both [(2,2-diphenyl-1-picrylhydrazyl)acid] radical (DPPH) and [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)] radical (ABTS) assays. In conclusion, winemaking from Magliocco dolce grape can provide potentially health-promoting by-products useful in cardiovascular disease management. [ABSTRACT FROM AUTHOR]

Polyphenols are well-known health promoting agents, but they have some limitations due to their spontaneous oxidation. This evidence has limited their use as drugs in recent years. In this field, several chemical modifications have been proposed to overcome these restrictions; among these, esterification seems to be the preferred modification. Ester derivatives may be able to reduce the bioavailability problems connected to polyphenols. On the other hand, the presence of esterase enzymes in the body guarantees ester hydrolysis, which in turn frees the two molecules that make it up. Lipase-catalyzed esterifications gave birth to several derivatives of flavonoids glycosides, in green conditions. In this short paper, pancreatic porcine lipase was firstly used as a cheap bio-catalyst, to synthesize oleoyl derivatives of quercetin in aglycone form. The results demonstrated how the enzyme is able to promote a regioselective acylation on C-3 position, with high yields and easy purification processes. [ABSTRACT FROM AUTHOR]

Cinnamic acid and its derivatives represent attractive building blocks for the development of pharmacological tools. A series of piperoniloyl and cinnamoyl‐based amides (6‐9 a‐f) have been synthesized and assayed against a wide panel of colorectal cancer (CRC) cells, with the aim of finding promising anticancer agents. Among all twenty‐four synthesized molecules, 7a, 7e‐f, 9c, and 9f displayed the best antiproliferative activity. The induced G1 cell cycle arrest and the increase in apoptotic cell death was seen in FACS analysis and western Blotting in the colon tumor cell lines HCT116, SW480, LoVo, and HT29, but not in the nontumor cell line HCEC. In particular, 9f overcame the resistance of HT29 cells, which have a mutant p53 and BRAF. Furthermore, 9f, amide of piperonilic acid with the 3,4‐dichlorobenzyl substituent upregulated p21, which is involved in cell cycle arrest as well as in apoptosis induction. Cinnamic acid derivatives might be potential anticancer compounds, useful for the development of promising anti‐CRC agents. [ABSTRACT FROM AUTHOR]

Bio‐based products are nowadays useful tools able to affect the productivity and quality of conventionally cultivated crops. Several bio‐based products are currently on the market; one of the newest and most promising is the wood distillate (WD) derived from the pyrolysis process of waste biomass after timber. Its foliar application has been widely investigated and shown to promote the antioxidant profile of cultivated crops. WD was used here as additive for the cultivation of tomato (Solanum lycopersicum L.) plants. The application improved quality (chemical) parameters, minerals, polyphenols, and lycopene contents of tomato fruits. The extracts of WD‐treated and untreated tomatoes have been chemically and biologically characterized. The 1H‐NMR and ESI‐mass spectrometry analyses of the extracts revealed the presence of different fatty acids, amino acids and sugars. In particular, the WD‐treated tomatoes showed the presence of pyroglutamic acid and phloridzin derivatives, but also dihydrokaempferol, naringenin glucoside, cinnamic acid, and kaempferol‐3‐O‐glucoside. When tested in cells, the extracts showed a promising anti‐inflammatory profile in lipopolysaccharide (LPS)‐stimulated RAW 264.7 macrophages. Furthermore, the extracts displayed a slight vasorelaxant activity on rat aorta rings (either endothelium‐denuded or endothelium‐intact) pre‐contracted with phenylephrine or potassium chloride. Practical Application: Wood distillate has been used for tomato plant growth. Tomatoes showed improved nutritional parameters, and their extracts displayed antioxidant and anti‐inflammatory activities. [ABSTRACT FROM AUTHOR]

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery. [Display omitted] • Patients with Chronic Lymphocytic Leukemia have apoptosis defects. • The apoptosis defects are caused in part by a reduced expression of p66Shc/STAT4. • HDAC1 inhibition as a strategy for reactivation of STAT4/p66Shc expression. • 6c (chlopynostat) is one of the most potent HDAC1 inhibitors. • 6c induces apoptosis via HDAC1 inhibition, reversing the STAT4/p66Shc defect. [ABSTRACT FROM AUTHOR]

[Display omitted] The progress made so far in the elucidation of the structure of free fatty acid receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

Site-Specific release of active molecules with antimicrobial activity spurred the interest in the development of innovative polymeric nanocarriers. In the preparation of polymeric devices, nanotechnologies usually overcome the inconvenience frequently related to other synthetic strategies. High performing nanocarriers were synthesized using a wide range of starting polymer structures, with tailored features and great chemical versatility. Over the last decade, many antimicrobial substances originating from plants, herbs, and agro-food waste by-products were deeply investigated, significantly catching the interest of the scientific community. In this review, the most innovative strategies to synthesize nanodevices able to release antimicrobial natural extracts were discussed. In this regard, the properties and structure of the starting polymers, either synthetic or natural, as well as the antimicrobial activity of the biomolecules were deeply investigated, outlining the right combination able to inhibit pathogens in specific biological compartments. [ABSTRACT FROM AUTHOR]

Summary: Seeds and skins from grape pomaces of Pecorello and Mantonico cv underwent extraction (ultrasound–assisted or maceration), in order to obtain added‐value ingredients for the production of a functional pear jam. The antioxidant features of the extracts were tested by in vitro colorimetric assays. Among seeds, Mantonico by maceration (MSC) showed the best results, as well as Mantonico by ultrasound‐assisted extraction (MBs) among skin extracts. The selected extracts were fully characterised by NMR and MS techniques, confirming the presence of many polyphenols, flavonoids and tannins among others. Pectin was then derivatised by the grafting procedure with the active molecules of MBs and MSC. The latter produced the best antioxidant polymer also without toxicity evaluated using Caco‐2 cells and was used for the jam preparation. The functional pear jam showed improved antioxidant performances in comparison with its non‐functional counterparts as well as its maintenance over time (15 days). [ABSTRACT FROM AUTHOR]

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a - t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e , 4g , 4n - o , and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e , 4n , and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e , 4g , 4n , and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation. [Display omitted] • New carbamate-based FAAH inhibitors endowed with improved solubility were developed. • Compounds were characterized as potent, selective, and reversible FAAH inhibitors. • Compounds prevented ROS formation in human astrocytes stressed with TBHP. • Neuroinflammatory damage was induced in hippocampal organotypic explants. • 4e, 4g, 4n, 4s exerted neuroprotection in LPS + IFN-γ-treated hippocampal explants. [ABSTRACT FROM AUTHOR]

The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual h HDAC6/ h HDAC8 inhibition profile were developed. The dual inhibitor design investigated the diphenyl-azetidin-2-one scaffold, typified in three different structural families, that, combined to a slender benzyl linker (6c , 6i , and 6j), displays nanomolar inhibition potency against h HDAC6 and h HDAC8 isoforms. Notably, their selective action was also corroborated by measuring their low inhibitory potency towards h HDAC1 and h HDAC10. Selectivity of these compounds was further demonstrated in human cell-based western blots experiments, by testing the acetylation of the non-histone substrates alpha-tubulin and SMC3. Furthermore, the compounds reduced the proliferation of colorectal HCT116 and leukemia U937 cells, after 48 h of treatment. The toxicity of the compounds was evaluated in rat perfused heart and in zebrafish embryos. In this latter model we also validated the efficacy of the dual h HDAC6/ h HDAC8 inhibitors against their common target acetylated-alpha tubulin. Finally, the metabolic stability was verified in rat, mouse, and human liver microsomes. [Display omitted] • Azetidin-2-one has been discovered as a new cap group for HDAC inhibition. • The new compounds showed a dual hHDAC6/HDAC8 inhibition profile. • The dual profile was confirmed by blotting non-histone proteins, such α-tubulin and SMC3. • 6c , 6i and 6j showed a good anti-proliferative effect in HCT116 and U937 cell lines. • Compounds showed no toxicity in rat perfused heart and danio rerio. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosome dependent cell survival mechanism and is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Targeting autophagy in cancer therapy attracted considerable attention in the past as stress-induced autophagy has been demonstrated to contribute to both drug resistance and malignant progression and recently interest in this area has re-emerged. Unlocking the therapeutic potential of autophagy modulation could be a valuable strategy for designing innovative tools for cancer treatment. Microtubule-targeting agents (MTAs) are some of the most successful anti-cancer drugs used in the clinic to date. Scaling up our efforts to develop new anti-cancer agents, we rationally designed multifunctional agents 5a-l with improved potency and safety that combine tubulin depolymerising efficacy with autophagic flux inhibitory activity. Through a combination of computational, biological, biochemical, pharmacokinetic-safety, metabolic studies and SAR analyses we identified the hits 5i,k. These MTAs were characterised as potent pro-apoptotic agents and also demonstrated autophagy inhibition efficacy. To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k , endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late-stage autophagy inhibitors by impairing autophagosome-lysosome fusion. [Display omitted] • New microtubule targeting agents were synthesized by using a hybridization approach. • Compounds are characterized by potent proapoptotic and autophagy inhibition efficacy. • Autophagic flux inhibition was confirmed by the expression of LC3II/LC3I and p62 proteins. • 5i and 5k are late-stage autophagy inhibitors impairing autophagosome-lysosome fusion. [ABSTRACT FROM AUTHOR]

• Pinocembrin was hybridized with fatty acids by using pancreatic porcine lipase. • Pinocembrin and its linolenoyl derivative promoted wound closure in HaCaT cells. • Wound healing activity was mediated by GPR120/β-arrestin complexation. • Wound healing was limited by pre-treatment with GPR120 antagonist AH7614. • Pinocembrin and its linolenoyl derivative share the same binding pocket of TUG-891. Wound healing represents an urgent need from the clinical point of view. Several diseases result in wound conditions which are difficult to treat, such as in the case of diabetic foot ulcer. Starting from there, the medicinal research has focused on various targets over the years, including GPCRs as new wound healing drug targets. In line with this, GPR120, known to be an attractive target in type 2 diabetes drug discovery, was studied to finalize the development of new wound healing agents. Pinocembrin (HW0) was evaluated as a suitable compound for interacting with GPR120, and was hybridized with fatty acids, which are known endogenous GPR120 ligands, to enhance the wound healing potential and GPR120 interactions. HW0 and its 7-linolenoyl derivative (HW3) were found to be innovative wound healing agents. Immunofluorescence and functional assays suggested that their activity was mediated by GPR120, and docking simulations showed that the compounds could share the same pocket occupied by the known GPR120 agonist, TUG-891. [ABSTRACT FROM AUTHOR]

Over the years secondary metabolites have been considered as lead molecules both in their natural form and as templates for medicinal chemistry. Some secondary metabolites such as polyphenols and flavan-3-ols exert beneficial effects after a modification by the microbiota. Synthetic precursors of some of these modified compounds, in turn, carried a γ-alkylidenebutenolide moiety which characterizes a large class of bioactive natural products endowed with a wide range of biological activities. For these reasons stereoselective preparation of γ-alkylidenebutenolide continues to be an important issue for organic chemists. Our objective is to synthetize the novel compound (Z)-5-(3′,4′-bis(benzyloxy)benzylidene)furan-2(5H)-one in a stereocontrolled-one-pot reaction. The product was obtained in good yield. Furthermore, the theoretical investigation of the transition states suggests a new procedure to achieve Z-isomer of β-unsubstituted γ-alkylidenebutenolide. [ABSTRACT FROM AUTHOR]