Explore the vast range of titles available.

Marine ecosystems represent an exceptional reservoir of structurally diverse metabolites with remarkable pharmacological potential. Over the past decades, the exploration of marine organisms has led to the discovery of an ever-expanding number of bioactive compounds. Many of these metabolites display highly original chemical scaffolds that are not typically found in terrestrial organisms, offering new opportunities for drug discovery. Among the most promising applications is their development as anticancer agents, given their ability to interfere with key cellular processes. This review highlights marine natural products currently under investigation in preclinical studies as potential anticancer lead compounds. The molecules are classified into major structural families: aromatic and heterocyclic alkaloids, terpenes and their derivatives, macrolide frameworks, and diverse peptide-based scaffolds, alongside other complex classes (polyketides, thiazole lipids, alkylamino alcohols, and pyrrolocarbazole derivatives). A particular emphasis has been placed on the role of total synthesis over the last decade. Advances in synthetic methodology have not only enabled the production of these complex metabolites in sufficient quantities but have also facilitated the development of novel chemotherapeutic agents. To overcome the challenges of limited natural availability, the advanced synthetic approaches are crucial for harnessing the full therapeutic potential of marine-derived compounds.

Vicia faba L. is a widely cultivated legume known to contain numerous specialised metabolites. In this study, the seed coats and cotyledons of two ancient V. faba L. varieties, historically consumed in southern Italy and distinguished by black and purple seed coats, were extracted using 80% methanol and 80% ethanol. Extracts were analysed for total polyphenol, flavonoid and proanthocyanidin contents, and antioxidant activity using DPPH, ABTS, and FRAP assays. The purple seed coats exhibited the highest levels of phenolics and antioxidant capacity, exceeding those of black seed coats. Next, liquid chromatography coupled with high-resolution mass spectrometry (LC-ESI-HR-MS) was used to characterise the bioactive metabolites in both seed coats and cotyledons. The purple variety showed a higher phytochemical content, with a greater level of flavonoids and proanthocyanidins in methanolic extract. Furthermore, the purple seed coat exhibited in vitro anti-inflammatory activity by inhibiting soluble epoxide hydrolase (sEH), a key enzyme in the arachidonic acid cascade, with an IC50 of 31.51 ± 1.16 µg/µL. Elemental analysis was performed for both varieties to assess their nutritional value. Specifically, the purple seed coats were found to represent a valuable source of bioactive compounds and micronutrients, highlighting their potential applications in nutraceutical, cosmetic, and food supplement sectors.

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds 2, 5, and 6 showed high affinity for BRD4, with IC50 values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure–activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.

Laurus nobilis L. is commonly used in folk medicine in the form of infusion or decoction to treat gastrointestinal diseases and flatulence as a carminative, antiseptic, and anti-inflammatory agent. In this study, the essential oil (EO) composition of wild-grown L. nobilis L. leaves collected from seven different altitudinal locations in the Molise region and adjacent regions (Abruzzo and Campania) was investigated. EOs from the leaves were obtained by hydrodistillation and analyzed by GC-FID and GC/MS, and 78 compounds were identified. The major oil components were 1,8-cineol (43.52–31.31%), methyl-eugenol (14.96–4.07%), α-terpinyl acetate (13.00–8.51%), linalool (11.72–1.08%), sabinene (10.57–4.85%), α-pinene (7.41–3.61%), eugenol (4.12–1.97%), and terpinen-4-ol (2.33–1.25%). Chemometric techniques have been applied to compare the chemical composition. To shed light on the nutraceutical properties of the main hydrophobic secondary metabolites (≥1.0%) of laurel EOs, we assessed the in vitro antioxidant activities based on 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging activity and the reducing antioxidant power by using a ferric reducing power (FRAP) assay. Furthermore, we highlighted the anti-inflammatory effects of seven EOs able to interfere with the enzyme soluble epoxide hydrolase (sEH), a key enzyme in the arachidonic acid cascade, in concentrations ranging from 16.5 ± 4.3 to 8062.3 ± 580.9 mg/mL. Thanks to in silico studies, we investigated and rationalized the observed anti-inflammatory properties, ascribing the inhibitory activity toward the disclosed target to the most abundant volatile phytochemicals (≥1.0%) of seven EOs.

The common bean (Phaseolus vulgaris L.) is one of the oldest food crops in the world. In this study, the ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) technique was used to characterize the polar lipid composition and polyphenolic fraction of five bean varieties commonly consumed in Italy: Cannellino (PVCA), Controne (PVCO), Borlotti (PVBO), Stregoni (PVST), and Vellutina (PVVE). Lipid content represents a minor fraction of the whole metabolome in dry beans, and little is known about their polar lipids, which could be potentially bioactive components. Thirty-three compounds were detected through UHPLC-MS/MS, including oxylipins, phospholipids, N-acyl glycerolipids, and several fatty acids. The dichloromethane extracts were subjected to principal component analysis (PCA), with the results showing greater differentiation for the Borlotti variety. Moreover, 27 components belonging to different polyphenol classes, such as phenolic acids, flavonoids, catechins, anthocyanins and their glycosides, and some saponins, were identified in the hydroalcoholic seed extracts. In addition, the mineral content of the beans was determined. Considering the high number of compounds in the five apolar seed extracts, all samples were examined to determine their in vitro inhibitory activity against the enzyme cyclooxygenase-2 (COX-2), which is inducible in inflammatory cells and mediates inflammatory responses. Only PVCO showed the best inhibition of the COX-2 enzyme with an IC50 = 31.15 ± 2.16 µg/mL. In light of these results, the potential anti-inflammatory properties of PVCO were evaluated in the LPS-stimulated murine macrophage cell line J774A.1. Herein, we demonstrate, for the first time, that PVCO at 30 µg/mL can significantly reduce the release of TNF-α, with a less significant anti-inflammatory effect being observed in terms of IL-6 release.

In this work, we report the identification of novel bromodomain‐containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure‐based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1‐ethyl‐1H‐pyrazolo[3,4‐b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C‐4 and C‐6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2–20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low‐micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target. A virtual screening based on our developed 3D structure‐based pharmacophore model led to the identification of compound 1, which showed promising binding affinity on the epigenetic reader bromodomain‐containing protein 9 (BRD9). Consequently, the 1‐ethyl‐1H‐pyrazolo[3,4‐b]pyridine motif was used as a new chemical scaffold for the design and synthesis of 19 derivatives. Four compounds displayed notable binding on BRD9, and among them, compound 5 exhibited cytotoxic activity against HeLa and A375 cancer cells.

In this work, we report the identification of novel bromodomain‐containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure‐based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit ( 1 ) featuring the 1‐ethyl‐1 H ‐pyrazolo[3,4‐ b ]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C‐4 and C‐6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives ( 2 – 20 ) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds ( 5 , 11 , 12 , and 19 ) stood out in biophysical assays as new valuable BRD9 ligands featuring IC 50 values in the low‐micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target.

In this work, we report the identification of novel bromodomain-containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure-based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1-ethyl-1H-pyrazolo[3,4-b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C-4 and C-6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2-20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low-micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target.In this work, we report the identification of novel bromodomain-containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure-based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1-ethyl-1H-pyrazolo[3,4-b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C-4 and C-6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2-20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low-micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target.

Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole‐based compounds was re‐investigated by IVS. Four items, originally synthesized and tested on bromodomain‐containing protein 9 (BRD9) but yielding poor binding, were critically re‐analyzed, disclosing only a partial fit with 3D structure‐based pharmacophore models, which, in the meanwhile, were developed for this target. Afterwards, these compounds were re‐evaluated through IVS on a panel of proteins involved in inflammation and cancer, identifying soluble epoxide hydrolase (sEH) as a putative interacting target. Three items were subsequently confirmed as able to interfere with sEH activity, leading to inhibition percentages spanning from 70 % up to 30 % when tested at 10 μM. Finally, one benzothiazole‐based compound emerged as the most promising inhibitor featuring an IC50 in the low micromolar range (IC50=6.62±0.13 μM). Our data confirm IVS as a predictive tool for accelerating the target identification and repositioning processes. The Inverse Virtual Screening (IVS) approach was used to re‐evaluate benzothiazole‐based compounds, which were initially designed for bromodomain‐containing protein 9 (BRD9) but resulted inactive. Applying the IVS on a customized panel containing proteins involved in cancer and inflammation, the soluble epoxide hydrolase (sEH) was predicted as one of the most promising, aiding the identification of a new sEH inhibitor.