Abstract Indazole-derived synthetic cannabinoids (SCs) featuring an alkyl substituent at the 1-position and l-valinamide at the 3-carboxamide position (e.g., AB-CHMINACA) have been identified by forensic chemists around the world, and are associated with serious adverse health effects. Regioisomerism is possible for indazole SCs, with the 2-alkyl-2H-indazole regioisomer of AB-CHMINACA recently identified in SC products in Japan. It is unknown whether this regiosiomer represents a manufacturing impurity arising as a synthetic byproduct, or was intentionally synthesized as a cannabimimetic agent. This study reports the synthesis, analytical characterization, and pharmacological evaluation of commonly encountered indazole SCs AB-CHMINACA, AB-FUBINACA, AB-PINACA, 5F-AB-PINACA and their corresponding 2-alkyl-2H-indazole regioisomers. Both regioisomers of each SC were prepared from a common precursor, and the physical properties, 1H and 13C nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry, and ultraviolet–visible spectroscopy of all SC compounds are described. Additionally, AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA were found to act as high potency agonists at CB1 (EC50 = 2.1–11.6 nM) and CB2 (EC50 = 5.6–21.1 nM) receptors in fluorometric assays, while the corresponding 2-alkyl-2H-indazole regioisomers demonstrated low potency (micromolar) agonist activities at both receptors. Taken together, these data suggest that 2-alkyl-2H-indazole regioisomers of AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are likely to be encountered by forensic chemists and toxicologists as the result of improper purification during the clandestine synthesis of 1-alkyl-1H-indazole regioisomers, and can be distinguished by differences in gas chromatography–mass spectrometry fragmentation pattern.

Extracellular signals drive the nucleation of the NLRP3 inflammasome which leads to the release of cytokines and causes inflammatory events. Hence, the inflammasome has gained enormous momentum in biomedical basic research. The detailed mechanisms of inflammasome generation and regulation remain to be elucidated. Our study was directed toward the design, convergent synthesis, and initial biochemical evaluation of activity-based probes addressing NLRP3. For this purpose, probes were assembled from a CRID3/MCC950-related NLRP3-binding unit, a linker portion and a coumarin 343 fluorophore or biotin. The affinity of our probes to NLRP3 was demonstrated through SPR measurements and their cellular activity was confirmed by reduction of the interleukin 1β release from stimulated bone marrow-derived macrophages. The initial characterizations of NLRP3-targeting probes highlighted the coumarin probe 2 as a suitable tool compound for the cellular and biochemical analysis of the NLRP3 inflammasome.

Several spectroscopic techniques have been optimized to check extra-virgin olive oil quality and authenticity, as well as to detect eventual adulterations. These methods are usually complementary and can give information about different olive oil chemical components with bioactive and antioxidant properties. In the present work, a well-characterized set of extra-virgin olive oil (cultivar Frantoio) samples from a specific area of Tuscany (Italy) were investigated by combining near UV-Vis absorption spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) to identify and quantify different chemical components, such as pigments, secoiridoids and squalene, related to the nutritional and quality properties of olive oils. Moreover, the pigmentation index of olives, organoleptic and sensory properties, total phenolic compound contents and the lipidic fractions of olive oils were investigated. The results obtained are, finally, compared and discussed in order to correlate several properties of both olives and olive oils with specific features of the cultivation area.

In this study, the Pluronic F127 with modified tripeptide Gly-Arg-Gly-Asp copolymer (hereafter defined as 3BE) hydrogel was evaluated in terms of its biocompatibility potentials. The fibroblasts (Swiss 3T3 cell line) and human hair follicles-derived mesenchymal stem cells (HFMSCs) were cultured in different concentrations of the 3BE hydrogel (0%, 0.05%, 0.1%, 0.25%, and 0.5%, respectively). The cell morphology and differentiation potential of HFMSCs were observed through optical microscopy, and the cell viability was investigated via Live/Dead Kit and Cell Counting Kit-8 assay. Analytical results showed that HFMSC can differentiate into adipogenic, chondrogenic, and osteogenic lineages. The HFMSC and Swiss 3T3 cells would properly assemble into a spherical shape as cultured with the 3BE hydrogel. Most importantly, cell viability could be maintained above 70%. The formation of spheroid structures of cells within this hydrogel is predicted to promote cell differentiation potentials of HFMSC that benefit in generating functional adipocytes, chondrocytes, and osteoblasts. Therefore, these findings demonstrate that the 3BE hydrogel has great potential as a three-dimensional cell culture scaffold for tissue engineering applications.

As part of our ongoing interest to identify bioactive chemical entities from marine invertebrates, the Red Sea specimen of the Verongid sponge Aplysinella species was studied. Repeated chromatographic fractionation of the methanolic extract of the sponge and HPLC purification of the cytotoxic fractions led to the isolation and the identification of two new compounds, psammaplysin Z and 19-hydroxypsammaplysin Z (1 and 2), together with the previously reported psammaplysins A (3) and E (4). The structural determination of 1–4 was supported by interpretation of their NMR and high-resolution mass spectra. Psammaplysins A and E displayed cytotoxic activity against MBA-MB-231 and HeLa cell lines with IC50 values down to 0.29 µM. On the other hand, psammaplysin Z and 19-hydroxypsammaplysin Z were moderately cytotoxic, indicating the importance of the terminal amine and 2-(methylene)cyclopent-4-ene-1,3-dione moieties in 3 and 4 for potent cytotoxic activity.

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC–BSA nanoparticles (NPs). These PIC–BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC–BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC–BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC–BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC–BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.

Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.

The lack of supported versions of the tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) ligand, suitable for flow-chemistry applications at scale, prompted us to develop a new route for the immobilization of such tris-triazole chelating units on highly cross-linked polystyrene resins. With this aim, the preparation of the known TBTA-type monomer 3 was optimized to develop a high-yield synthetic sequence, devoid of chromatographic purifications at any stage. Then, bead-type (P7) and monolithic (M7) functional resins were obtained by the easy and scalable suspension- or mold-copolymerization of 3 with divinylbenzene. Both types of materials were found to possess a highly porous morphology and specific surface area in the dry state and could be charged with substantial amounts of Cu(I) or Cu(II) salts. After treatment of the latter with a proper reducing agent, the corresponding supported Cu(I) complexes were tested in the copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC). The immobilized catalysts proved active at room temperature and, in batch and with catalyst loadings as low as 0.6 mol%, afforded quantitative conversions within 20 h. Independent of the alkyne structure, extended use of the supported catalyst in flow was also possible. In the reaction of benzylazide and propargyl alcohol, this allowed a total turnover number larger than 400 to be reached.

A library of pinane-based chiral aminodiols, derived from natural (−)-β-pinene, were prepared and applied as chiral catalysts in the addition of diethylzinc to aldehydes. (−)-β-Pinene was reacted to provide 3-methylenenopinone, followed by a reduction of the carbonyl function to give a key allylic alcohol intermediate. Stereoselective epoxidation of the latter and subsequent ring opening of the resulting oxirane with primary and secondary amines afforded aminodiols. The regioselectivity of the ring closure of the N-substituted secondary aminodiols with formaldehyde was examined and exclusive formation of oxazolidines was observed. Treatment of the allylic alcohol with benzyl bromide provided the corresponding O-benzyl derivative, which was transformed into O-benzyl aminodiols by aminolysis. Ring closure of the N-isopropyl aminodiol derivative with formaldehyde resulted in spirooxazolidine. The obtained potential catalysts were applied in the reaction of both aromatic and aliphatic aldehydes to diethylzinc providing moderate to good enantioselectivities (up to 87% ee). Through the use of molecular modeling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modeling at the RHF/LANL2DZ level of theory was successfully applied for interpretation of the stereochemical outcome of the reactions leading to display excellent (R) enantioselectivity in the examined transformation.

PEGylated imidazolium (bromide and tetrafluoroborate) and tris-imidazolium (bromide) salts containing triazole linkers have been used as stabilizers for the preparation of water-soluble rhodium(0) nanoparticles by reduction of rhodium trichloride with sodium borohydride in water at room temperature. The nanomaterials have been characterized (Transmission Electron Microscopy, Electron Diffraction, X-ray Photoelectron Spectroscopy, Inductively Coupled Plasma-Optical Emission Spectroscopy). They proved to be efficient and recyclable catalysts for the stereoselective hydrosilylation of internal alkynes, in the presence or absence of solvent, and in the reduction of nitroarenes to anilines with ammonia-borane as hydrogen donor in aqueous medium (1:4 tetrahydrofuran/water).

A possible approach for enhancement of Poly(vinyl alcohol) (PVA) humidity-sensing performance using hydrophobically modified PVA copolymers is studied. Series of poly(vinylalcohol-co-vinylacetal)s (PVA–Ac) of acetal content in the range 18%–28% are synthesized by partial acetalization of hydroxyl groups of PVA with acetaldehyde and thin films are deposited by spin-coating using silicon substrates and glass substrates covered with Au–Pd thin film with thickness of 30 nm. Sensing properties are probed through reflectance measurements at relative humidity (RH) in the range 5%–95% RH. The influence of film thickness, post-deposition annealing temperature, and substrate type/configuration on hysteresis, sensitivity, and accuracy/resolution of humidity sensing is studied for partially acetalized PVA copolymer films, and comparison with neat PVA is made. Enhancement of sensing behavior through preparation of polymer–silica hybrids is demonstrated. The possibility of color sensing is discussed.

New epoxy resin hardeners were prepared from the reaction of p-nonylphenol and cardanol glycidylether with pentaethylenehexamine (PEHA) to produce hydrophobic polyamines. They were used as capping to produce superhydrophobic magnetite nanoparticles (Fe3O4 NPs). The chemical structures, thermal stability, morphologies, and particle sizes diameters were evaluated to confirm the hydrophobicity of dicardanoxy (DCHI) and dinonylphenoxy (HPHI) polyamines. The curing exothermic reaction of bisphenol A diglycidyl ether (DGEB) epoxy resin with DCHI, HPHI, or their Fe3O4 NPs was investigated by dynamic mechanical analyzer and differential scanning calorimetry. The cured epoxy networks crosslinking densities, storage modulus, and glass transition temperatures were determined and correlated to epoxy networks chemical compositions. DGEB/DCHI and DGEB/HPHI with their stoichiometric ratio embedded with their Fe3O4 NPs were applied on the rough steel surface to produce hydrophobic and superhydrophobic epoxy coatings. The wetting characteristics of the cured epoxy nanocomposites were evaluated from seawater contact angle (WCA) measurements to prove the formation of superhydrophobic coatings in the presence of DCHI-Fe3O4 NPs having WCA > 150°. The excellent adhesion, mechanical, and anti-corrosion performances using DGEB/DCHI and DGEB/HPHI epoxy nanocomposites were obtained on the steel surfaces in the presence of seawater corrosive environment.

Modification of the curing exothermic reaction of epoxy resin with polyamine (PA) hardeners by new chemically bonded fillers to improve the mechanical properties and anticorrosion performances of the epoxy coatings is the main goal for wide applications of epoxy coatings. In this work, the chemical structure of chitosan was modified with triazine hydrazide moiety that contains primary, secondary, and tertiary amine groups to act as activator and dangling chain linkers during the curing of epoxy/PA system. Different molecular masses of chitosan were modified with triazine dihydrazide moiety (Ch-TH2), and their chemical structures and surface morphologies were identified. Their thermal stabilities were investigated, and the grafting percentages with triazine hydrazide were determined from thermal analysis. Different weight percentages of Ch-TH2 ranged from 1 to 10 Wt. % were added to the epoxy/PA system, and their curing characteristics, such as heat enthalpy and glass transition temperature, were determined from non-isothermal dynamic scanning calorimetric thermograms. The effects of molecular masses, triazine dihydrazide %, and Ch-TH2 Wt. % on the mechanical, adhesion and anticorrosive properties of the cured epoxy/PA coatings for steel were investigated. The optimum Ch-TH2 Wt. % was selected from 3 to 6 Wt. % to improve the mechanical, adhesion, and anticorrosive properties of the cured epoxy/PA coatings.

An unusual self-assembled hetero-bimetallic [Ni(II)-Sm(III)] coordination polymer, [Ni(L)Sm(NO3)3(4,4′-bipy)]n, is prepared through a hexadentate chelating ligand 2,2′-[1,2-ethylenedioxybis(nitrilomethylidyne)]diphenol (H2L). The Ni(II)-Sm(III) coordination polymer is validated through elemental analyses, Fourier-transform infrared and UV-Visible spectroscopies, and X-ray single-crystal diffraction. The Ni(II) atom forms a twisted six-coordinated octahedron, and the Sm(III) atom is ten-coordinated, adopting a twisted bicapped square antiprism. An infinite three-dimensional-layer supramolecular structure is obtained through extensive π···π stacking and intermolecular hydrogen bonding interactions. The polymer has a good antibacterial effect against Staphylococcus aureus.

A unprecedented hetero-bimetallic 3d-4f BDC-salamo-based coordination polymer, [(L)Ni(BDC)Gd(NO3)(DMF)] was prepared and validated via elemental analyses, IR and UV–Visible absorption spectra, DFT calculation, and X-ray crystallography. The six-coordinated Ni1 ion lies at the N2O2 donor site of the L2− moiety, and one DMF O atom and carboxylate O atom occupy, collectively, the axial positions, and form a twisted octahedron. The nine-coordinated Gd1 ion consists of three oxygen atoms (O12, O13, and O14) of two carboxylate groups, two oxygen atoms (O8 and O9) derived from one bidentate nitrate group, and an O2O2 coordination site (O1, O2, O6, and O5) of the L2− unit, forming a twisted three-capped triangular prism coordination geometry. Compared to the ligand (H2L), the fluorescence intensity decreases due to the coordination of metal ions. Meanwhile, the antibacterial activities are researched.

The main objectives of the current work were to investigate differences among flours from traditionally preserved Greek varieties of cereals, and especially those of wheat, and in parallel, to correlate those potential differences with the presence of bioactive natural ingredients. In this context, we developed a new, fast, and simple method for the measurement of total 5-alkylresorcinols in cereals and related foods by qNMR. Several types of flour (white or whole-grain) coming from wheat, i.e., Triticum dicoccum, T. monococcum, T. aestivum, T. durum and T. turgidum, corn, barley, rye and oat from a certified producer in Greece were used either as raw materials or for the production of bread, pasta and flakes. A small portion of the flour or the corresponding product was extracted with DMSO-d6. The liquid part was directly analyzed by NMR (400 MHz). The simplicity of the NMR spectrum of the total extract and the lack of overlapping peaks permitted the development of a high throughput quantitative method for the measurement of total bioactive alkylresorcinols in less than 15 min. Grains, whole grain flours and breads from old varieties of T. dicoccum and T.monococcum showed high contents of alkylresorcinols (455–1148 mg/Kg), while the same compounds were completely absent from white flour and the corresponding bread. The term high-phenolic flour is proposed to distinguish among flour types.

Due to its structural similarity, the α’-1′-hydroxyethyl-γ-butyrolactone obtained by reduction of (±)-α-acetyl-γ-butyrolactone may have a similar function in the body to γ-butyrolactone (GBL). In the work presented, biotransformation of α-acetyl-γ-butyrolactone by three Rhodotorula strains was performed obtaining enantiomerically enriched alcohol. The process was carried out in growing and resting cultures. We studied how both media composition and organic solvent volume affected stereoselectivity and effectiveness of biotransformation. After 2 h, the enantiomerically pure (3R, 1′S)-α’-1′-hydroxyethyl-γ-butyrolactone was obtained using the R. marina AM77 strain in YPG (Yeast extract-Peptone-Glucose) medium enriched with 5% glycerol. To our best knowledge there is no previous information in the literature about the (±)-α-acetyl-γ-butyrolactone biotransformation performed in medium with addition of organic and deep eutectic solvents.

The 191-residue-long LrtA protein of Synechocystis sp. PCC 6803 is involved in post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family, intervening in protein synthesis. The protein consists of two domains: The N-terminal region (N-LrtA, residues 1101), which is common to all the members of the HPF, and seems to be well-folded; and the C-terminal region (C-LrtA, residues 102-191), which is hypothesized to be disordered. In this work, we studied the conformational preferences of isolated C-LrtA in solution. The protein was disordered, as shown by computational modelling, 1D-1H NMR, steady-state far- UV circular dichroism (CD) and chemical and thermal denaturations followed by fluorescence and far-UV CD. Moreover, at physiological conditions, as indicated by several biochemical and hydrodynamic techniques, isolated C-LrtA intervened in a self-association equilibrium, involving several oligomerization reactions. Thus, C-LrtA was an oligomeric disordered protein.

The rhizoma of Ligusticum sinense, a Chinese medicinal plant, has long been used as a cosmetic for the whitening and hydrating of the skin in ancient China. In order to investigate the antimelanogenic components of the rhizoma of L. sinense, we performed an antimelanogenesis assay-guided purification using semi-preparative HPLC accompanied with spectroscopic analysis to determine the active components. Based on the bioassay-guided method, 24 compounds were isolated and identified from the ethyl acetate layer of methanolic extracts of L. sinense, and among these, 5-[3-(4-hydroxy-3-methoxyphenyl)allyl]ferulic acid (1) and cis-4-pentylcyclohex-3-ene-1,2-diol (2) were new compounds. All the pure isolates were subjected to antimelanogenesis assay using murine melanoma B16-F10 cells. Compound 1 and (3S,3aR)-neocnidilide (8) exhibited antimelanogenesis activities with IC50 values of 78.9 and 31.1 μM, respectively, without obvious cytotoxicity. Further investigation showed that compound 8 demonstrated significant anti-pigmentation activity on zebrafish embryos (10‒20 μM) compared to arbutin (20 μM), and without any cytotoxicity against normal human epidermal keratinocytes. These findings suggest that (3S,3aR)-neocnidilide (8) is a potent antimelanogenic and non-cytotoxic natural compound and may be developed potentially as a skin-whitening agent for cosmetic uses.

Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. Tert-butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity.