The effects of histidine substitution of aromatic residues on the amyloidogenic properties of the fragment 264-277 of nucleophosmin 1.

Histidine (His) plays a key role in mediating protein interactions and its unique side chain determines pH responsive self-assembling processes and thus in the formation of nanostructures. In this study, To identify novel self-assembling bioinspired sequences, we analyzed a series of peptide sequences obtained through the point mutation of aromatic residues of 264-277 fragment of nucleophosmin 1 (NPM1) with single and double histidines. Through several orthogonal biophysical techniques and under different pH and ionic strength conditions we evaluated the effects of these substitutions in the amyloidogenic features of derived peptides. The results clearly indicate that both the type of aromatic mutated residue and its position can have different effect on amyloid-like behaviors. They corroborate the crucial role exerted by Tyr271 in the self-assembling process of CTD of NPM1 in AML mutated form and add novel insights in the accurate investigation of how side chain orientations can determine successful design of innovative bioinspired materials.

3-Nitroatenolol: First Synthesis, Chiral Resolution and Enantiomers' Absolute Configuration.

4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera's method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined.

Domino synthesis of 5-aminoimidazoles from Strecker multicomponent adducts via ytterbium-promoted isocyanide insertion/5-exo-dig cyclization.

A new Lewis acid promoted domino isocyanide insertion/5-exo-dig cyclization of readily available Strecker 3-component adducts to 4-substituted 5-aminoimidazole derivatives is herein reported. Despite their potential as relevant heterocyclic scaffolds in medicinal chemistry programs, this class of compounds is still underrepresented, with current synthetic strategies poorly efficient in terms of timing and yields. To this end, we show how the exploitation of unconventional reactivities of isocyanides, promoted by ytterbium-triflate, could represent a key resource to enable a fast and easy access to such an unexplored area of the chemical space.

Thyroid Hormone Regulates the Lipid Content of Muscle Fibers, Thus Affecting Physical Exercise Performance.

Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology.

Synthesis, Chiral Resolution and Enantiomers Absolute Configuration of 4-Nitropropranolol and 7-Nitropropranolol.

We recently identified 6-nitrodopamine and other nitro-catecholamines (6-nitrodopa, 6-nitroadrenaline), indicating that the endothelium has the ability to nitrate the classical catecholamines (dopamine, noradrenaline, and adrenaline). In order to investigate whether drugs could be subject to the same nitration process, we synthesized 4-nitro- and 7-nitropropranolol as probes to evaluate the possible nitration of the propranolol by the endothelium. The separation of the enantiomers in very high yields and excellent enantiopurity was achieved by chiral HPLC. Finally, we used Riguera's method to determine the absolute configuration of the enantiomers, through double derivatization with MPA and NMR studies.

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2-Carboxamide Nucleus.

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study.

Antiproliferative Illudalane Sesquiterpenes from the Marine Sediment Ascomycete Aspergillus oryzae.

The new asperorlactone (1), along with the known illudalane sesquiterpene echinolactone D (2), two known pyrones, 4-(hydroxymethyl)-5-hydroxy-2H-pyran-2-one (3) and its acetate 4, and 4-hydroxybenzaldehyde (5), were isolated from a culture of Aspergillus oryzae, collected from Red Sea marine sediments. The structure of asperorlactone (1) was elucidated by HR-ESIMS, 1D, and 2D NMR, and a comparison between experimental and DFT calculated electronic circular dichroism (ECD) spectra. This is the first report of illudalane sesquiterpenoids from Aspergillus fungi and, more in general, from ascomycetes. Asperorlactone (1) exhibited antiproliferative activity against human lung, liver, and breast carcinoma cell lines, with IC50 values < 100 µM. All the isolated compounds were also evaluated for their toxicity using the zebrafish embryo model.

Photocatalytic Isocyanide-Based Multicomponent Domino Cascade toward the Stereoselective Formation of Iminofurans.

A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.

Glycosylated Phenols and an Unprecedented Diacid from the Saudi Plant Cissus rotundifolia.

Bioassay-guided investigation of the Saudi medicinal and edible plant Cissus rotundifolia yielded seven metabolites, including the new sucrose diester cissuxinoside (1) and the unprecedented cissoic acid (2), belonging to unusual classes of secondary metabolites. Their chemical structures were elucidated through a combination of HR-MS and NMR data. The absolute configuration of cissoic acid was assigned by comparison of experimental and TDDFT-calculated electronic circular dichroism spectra. In addition, three rare C-glycosyl flavones (3-5) were fully characterized, and for 3 and 4 NMR data are reported here for the first time. This study identified 1-O-(4-coumaroyl)-ß-d-glucopyranose (7) as the main compound responsible for the glucose uptake stimulation effect exerted by the extract.

Penipyranicins A-C: Antibacterial Methylpyran Polyketides from a Hydrothermal Spring Sediment Penicillium sp.

Four new aromatic polyketides (1-4) were isolated from Penicillium sp. RO-11, obtained from the sediment of a hydrothermal spring in the southwestern region of Saudi Arabia. The new compounds are penipyranicins A-C (1-3), characterized by a 4-methyl-4H-pyran moiety, a structural motif unprecedented among fungal polyketides, and the naphthopyrone derivative isopyrenulin (4). The structures of the new compounds were elucidated on the basis of data from mass spectrometry, 1D and 2D NMR analysis, and comparison between experimental and time-dependent density functional theory-calculated electronic circular dichroism spectra. A plausible biosynthetic pathway connecting penipyranicins and isopyrenulin is proposed. The isolated compounds were active against Gram-positive and Gram-negative bacteria.

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone.

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.

Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate.

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.

Chemical Investigation of the Indonesian Tunicate Polycarpa aurata and Evaluation of the Effects Against Schistosoma mansoni of the Novel Alkaloids Polyaurines A and B.

A deep study of the metabolic content of the tunicate Polycarpa aurata, collected from Indonesian coast, afforded the isolation of two novel alkaloids, polyaurines A (1) and B (2), along with two new p-substituted benzoyl derivatives (3 and 4) and four known compounds (5-8). The structural elucidation of the new secondary metabolites was assigned by 1D, 2D NMR, and HRESIMS techniques. Computational studies resulted a useful tool to unambiguously determine in polyaurine B the presence of rarely found 1,2,4-thiadiazole ring. The effects of polyaurines A and B on mammalian cells growth and on the viability of different blood-dwelling Schistosoma mansoni (phylum: Platyhelminthes) stages, as well as egg production, were evaluated. Both compounds resulted not cytotoxic; interestingly some of the eggs produced by polyaurine A-treated adult pairs in vitro are smaller, deformed, and/or fragmented; therefore, polyaurine A could represent an interesting bioactive natural molecule to be further investigated.

In Vitro Antiproliferative Evaluation of Synthetic Meroterpenes Inspired by Marine Natural Products.

Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of the substituent groups in the quinone moiety. Aiming to broaden the knowledge of the underlying mechanism of the antiproliferative effect of these prenylated compounds, herein we report the synthesis of two quinones 4 and 5 and of their corresponding dioxothiazine fused quinones 6 and 7 inspired to the marine natural product aplidinone A (1), a geranylquinone featuring the 1,1-dioxo-1,4-thiazine ring isolated from the ascidian Aplidium conicum. The potential effects on viability and proliferation in three different human cancer cell lines, breast adenocarcinoma (MCF-7), pancreas adenocarcinoma (Bx-PC3) and bone osteosarcoma (MG-63), were investigated. The methoxylated geranylquinone 5 exerted the highest antiproliferative effect exhibiting a comparable toxicity in all three cell lines analyzed. Interestingly, a deeper investigation has highlighted a cytostatic effect of quinone 5 referable to a G0/G1 cell-cycle arrest in BxPC-3 cells after 24 h treatment.

The predictive power of transcranial sonography in movement disorders: a longitudinal cohort study.

Transcranial sonography (TCS) is a noninvasive, easily performed, and commonly available neuroimaging technique useful for the study of brain parenchyma in movement disorders. This tool has been increasingly used in the diagnosis of Parkinson's disease and atypical parkinsonism. The aim of the study was to evaluate the applicability of this technique as supportive tool in the early diagnosis of movement disorders. We performed TCS on 315 individuals which were diagnosed as healthy controls or affected by idiopathic Parkinson's disease, monogenetic subtypes of Parkinson's disease, atypical parkinsonism, and Dementia with Lewy bodies. Five TCS diagnostic patterns were defined on the basis of substantia nigra's and lenticular nuclei's echogenicity. TCS evaluations were performed by two blinded neuro-sonographers. Clinical diagnosis on all individuals was performed at baseline and at 4-year follow-up. The concordance rate between TCS patterns and clinical diagnosis and the specificity of TCS pattern to discriminate each group of individuals were compared at baseline and at follow-up. The concordance rate between TCS patterns and clinical diagnosis of all individuals was 84% at baseline and increased at follow-up (91%) significantly (p = 0.01). The specificity of TCS pattern in the comparison between patients diagnosed as affected by idiopathic Parkinson's disease and atypical parkinsonism showed a significant increase at follow-up (p = 0.03). Our study strongly confirms the role of TCS as a noninvasive and cost-effective tool in early diagnosis of movement disorders.

Assignment of the Absolute Configuration of Phosphoeleganin via Synthesis of Model Compounds.

The full absolute configuration assignment of phosphoeleganin (1), a recently discovered marine-derived phosphorylated polyketide with protein tyrosine phosphatase 1B inhibitory activity, was achieved. It was based on the synthesis of model diasteroisomeric compounds of the C-8-C-12 segment portion of phosphoeleganin, chiral derivatization methods, and application of the universal NMR database concept.

Antiprotozoal Linear Furanosesterterpenoids from the Marine Sponge Ircinia oros.

Chemical investigation of the marine sponge Ircinia oros yielded four linear furanosesterterpenoids, including the known metabolites ircinin-1 (1) and ircinin-2 (2) and two new compounds, ircinialactam E (3) and ircinialactam F (4). Their chemical structures were elucidated by using a combination of [α]D, NMR, HRMS, and FT-IR spectroscopy. The absolute configuration of C-18 in compounds 1-3 was identified as R by electronic circular dichroism (ECD) spectroscopy coupled with time-dependent density functional theory calculations. Compounds 1-4 showed moderate leishmanicidal, trypanocidal, and antiplasmodial activities (IC50 values 28-130 µM). This is the second report of rare glycinyl lactam derivatives 3 and 4 from the genus Ircinia.

Angeloylated Germacranolides from Daucus virgatus and Their Plasmodium Transmission Blocking Activity.

Phytochemical investigation of the aerial parts of the Tunisian plant Daucus virgatus led to the isolation of eight new germacranolides named daucovirgolides A-H (1-8). The stereostructures of these sesquiterpene lactones, decorated by either one or two angeloyl groups, have been determined by a combination of MS, NMR spectroscopy, chemical derivatization, and comparison of experimental electronic circular dichroism curves with TDDFT-predicted data. Daucovirgolide G (7) proved to be the single member of this family to possess a marked inhibitory activity (92% at 50 µg/mL) on the development of Plasmodium early sporogonic stages, the nonpathogenic transmissible stages of malaria parasites, devoid of general cytotoxicity. The selective activity of daucovirgolide G points to the existence of strict structural requirements for this transmission-blocking activity and therefore of a well-defined, although yet unidentified, biological target.

PPAR Modulating Polyketides from a Chinese Plakortis simplex and Clues on the Origin of Their Chemodiversity.

Fifteen polyketides, including the first hydroxylated plakortone (12) and plakdiepoxide (15), the first polyketide to embed a vicinal diepoxide, have been isolated from the Chinese sponge Plakortis simplex. The structures of the new metabolites were elucidated by analysis of spectroscopic data, Mosher's derivatization, and DFT computational calculations. The reactivity of the major endoperoxide of this sponge was investigated, suggesting that furan, furanylidene, and plakilactone derivatives, well-known classes of natural products, could actually be chemical degradation products. Plakdiepoxide is a potent and selective modulator of peroxisome proliferator-activated receptor (PPAR)-γ, while the diunsaturated C12 fatty acid monotriajaponide (13) activates both PPAR-α and PPAR-γ, a dual activity of potential great importance for the treatment of metabolic disorders.

Structure and Configuration of Phosphoeleganin, a Protein Tyrosine Phosphatase 1B Inhibitor from the Mediterranean Ascidian Sidnyum elegans.

A new phosphorylated polyketide, phosphoeleganin (1), has been isolated from the Mediterranean ascidian Sidnyum elegans. Its structure and configuration have been determined by extensive use of 2D NMR and microscale chemical degradation and/or derivatization. Phosphoeleganin (1) inhibited the protein tyrosine phosphatase 1B (PTP1B) activity.