Publications by authors named "Gianluca Giorgi"

115 Publications

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents.

ACS Chem Neurosci 2021 05 23;12(9):1716-1736. Epub 2021 Apr 23.

Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD2080 Msida, Malta.

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor . When tested in two rodent models of epilepsy, reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (-). Biological studies highlighted and as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, and could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for (Langendorff perfused rat heart). Finally, the new analogue reduced the severity of the pilocarpine-induced status epilepticus as observed for .
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http://dx.doi.org/10.1021/acschemneuro.1c00192DOI Listing
May 2021

On the Transition from a Biomimetic Molecular Switch to a Rotary Molecular Motor.

J Phys Chem Lett 2021 Apr 15;12(16):3875-3884. Epub 2021 Apr 15.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy.

The experimental investigation of the unidirectional motion characterizing the photoisomerization of single-molecule rotary motors requires accessible lab prototypes featuring an electronic circular dichroism (ECD) signal that is sensitive to the geometrical and electronic changes occurring during an ultrafast reactive process. Here we report a combined experimental/computational study of a candidate obtained via the asymmetrization of a light-driven biomimetic molecular switch. We show that the achieved motor has an ECD band that is remarkably sensitive to the isomerization motion, and it is therefore suitable for time-resolved ECD studies. However, we also find that, unexpectedly, the synthesized motor isomerizes on a time scale longer than the subpicosecond time measured for the achiral parent, a result that points to alternative candidates conserving a high reaction speed.
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http://dx.doi.org/10.1021/acs.jpclett.1c00526DOI Listing
April 2021

Laccase-Catalyzed 1,4-Dioxane-Mediated Synthesis of Belladine -Oxides with Anti-Influenza A Virus Activity.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.

Belladine -oxides active against influenza A virus have been synthetized by a novel laccase-catalyzed 1,4-dioxane-mediated oxidation of aromatic and side-chain modified belladine derivatives. Electron paramagnetic resonance (EPR) analysis confirmed the role of 1,4-dioxane as a co-oxidant. The reaction was chemo-selective, showing a high functional-group compatibility. The novel belladine -oxides were active against influenza A virus, involving the early stage of the virus replication life cycle.
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http://dx.doi.org/10.3390/ijms22031337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866262PMC
January 2021

Synthesis of Polycyclic Fused Indoline Scaffolds through a Substrate-Guided Reactivity Switch.

J Org Chem 2020 09 21;85(17):11409-11425. Epub 2020 Aug 21.

Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies, University of Urbino "Carlo Bo", Via I Maggetti 24, 61029 Urbino, Italy.

Zn(II)-catalyzed divergent synthesis of functionalized polycyclic indolines through formal [3 + 2] and [4 + 2] cycloadditions of indoles with 1,2-diaza-1,3-dienes (DDs) is reported. The nature and type of substituents of substrates are found to act as a chemical switch to trigger two distinct reaction pathways and to obtain two different types of products upon the influence of the same catalyst. The mechanism of both [4 + 2] and [3 + 2] cycloadditions was investigated and fully rationalized by density functional theory (DFT) calculations.
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http://dx.doi.org/10.1021/acs.joc.0c01489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010796PMC
September 2020

Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.

J Med Chem 2020 07 22;63(13):7369-7391. Epub 2020 Jun 22.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
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http://dx.doi.org/10.1021/acs.jmedchem.0c00595DOI Listing
July 2020

Design, synthesis and biological evaluation of 7-substituted 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f] [1,4]diazepines as safe anxiolytic agents.

Eur J Med Chem 2020 Aug 18;200:112405. Epub 2020 May 18.

Dipartimento di Biotecnologie, Chimica e Farmacia, (Dipartimento d'Eccellenza 2018-2022), Università di Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address:

A series of 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylate esters were synthesized and tested as central benzodiazepine receptor (CBR) ligands by the ability to displace [H]flumazenil from rat cortical membranes. All the compounds showed high affinity with IC values ranging from 5.19 to 16.22 nM. In particular, compounds 12b (IC = 8.66 nM) and 12d (IC = 5.19 nM) appeared as the most effective ligands being their affinity values significantly lower than that of diazepam (IC = 18.52 nM). Compounds 12a-f were examined in vivo for their pharmacological effects in mice and five potential benzodiazepine (BDZ) actions were thus taken into consideration: anxiolytic, anticonvulsant, anti-amnesic, hypnotic, and locomotor activities. All the new synthesized compounds were able to induce a significant antianxiety effect and, among them, compound 12f protected pentylenetetrazole (PTZ)-induced convulsions in a dose-dependent manner reaching a 40% effect at 30 mg/kg. In addition, all the compounds were able to significantly prevent the memory impairment evoked by scopolamine, while none of them was able to interfere with pentobarbital-evoked sleep and influence motor coordination. Moreover, title compounds did not affect locomotor and exploratory activity at the same time and doses at which the anti-anxiety effect was observed. Finally, molecular docking simulations were carried out in order to assess the binding mode for compounds 12a-f. The obtained results demonstrated that these compounds bind the BDZ binding site in a similar fashion to flumazenil.
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http://dx.doi.org/10.1016/j.ejmech.2020.112405DOI Listing
August 2020

Characterization of additives in plastics: From MS to MS multistep mass analysis and theoretical calculations of tris(2,4-di-tert-butylphenyl)phosphate.

J Mass Spectrom 2020 Jun;55(6):e4515

National Research Council (CNR), Institute of Biology and Agricultural Biotechnology, Research Area of Pisa, Via Moruzzi 1, I-56124, Pisa, Italy.

In the analysis by electrospray (+) of an extract of hemp sprouts put in a polypropylene vial, we found a large contamination of a plastic additive. It was characterized by multiple-stage MS experiments (MS ÷ MS ) and identified as tris(2,4-di-tert-butylphenyl)phosphate, also known with the synonyms F32IRS6B46, oxidized Naugard 524, and others. The MS ÷ MS spectra are characterized by consecutive eliminations of six isobutene molecules from the tert-butyl moieties, some of them also occurring in the ion source. The first three are calculated to occur preferentially from the ortho positions, whereas eliminations from the para positions are estimated to be less favored at about 5-6 kcal/mol in each step. Once the first three isobutene molecules are eliminated, the remaining three are lost from the tert-butyl moieties in para positions (MS ÷ MS ), yielding protonated triphenylphosphate, whose structure has been confirmed by the MS spectrum of triphenylphosphate standard: the latter spectrum is almost superimposable with the MS spectrum of the analyte under investigation. MS and MS spectra show main losses of water and C H molecules. The MS spectrum of precursor ions at m/z 215 shows the gas-phase addition of water and methanol and ions at m/z 168, attributable to the loss of a phosphorus oxide radical. Density functional theory (DFT) calculations (Becke 3LYP [B3LYP] 6-311+G(2d,2p)) have been used to evaluate structure and stability of different ionic and neutral species involved in the decomposition pathways and to calculate thermochemical data of the decomposition reactions. This multistep mass analysis combined with theoretical calculations resulted to be particularly useful and effective, yielding chemical, thermochemical, and mechanistic data of significant utility in the structural characterization and identification of the unknown analyte as well as to define its gas-phase reactivity under a multistep low-energy collision-induced dissociation regime.
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http://dx.doi.org/10.1002/jms.4515DOI Listing
June 2020

Sangiovese Pomace Seeds Extract-Fortified Kefir Exerts Anti-Inflammatory Activity in an Model of Intestinal Epithelium Using Caco-2 Cells.

Antioxidants (Basel) 2020 Jan 8;9(1). Epub 2020 Jan 8.

Dipartimento di Farmacia e Scienze della Salute e della Nutrizione-Dipartimento di Eccellenza 2018-2022, Università della Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy.

Inflammatory bowel disease and food allergies are a growing topic in the field of nutrition science. Polyphenols, which are the most important secondary metabolites of plants, demonstrated to modulate the expression and/or production of numerous proteins, but also to regulate the intestinal ecosystem. In this context, our aim was the investigation of protective effects against the gastrointestinal mucosa of fortified milk kefir obtained by adding seeds extract from Sangiovese . Pomace. Methods: An ultrasound-assisted method was used to obtain the extracts. All the extracts were assayed for the antioxidant activity. The best extract was used as an additive of fermented milk kefir to obtain a fortified final product. Kefir samples were analyzed by NMR spectroscopy. The efficiency of the barrier functions was evaluated by measuring trans-epithelial electric resistance (TEER) using a voltmeter. Results: the enriched kefir (Ksgn) possesses higher antioxidant performances compared to the unfortified sample (Kwht). Kwht and Ksgn did not alter Caco-2 TEER in basal condition.
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http://dx.doi.org/10.3390/antiox9010054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022605PMC
January 2020

Physicochemical Properties of A New PEGylated Polybenzofulvene Brush for Drug Encapsulation.

Pharmaceutics 2019 Sep 1;11(9). Epub 2019 Sep 1.

Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022), Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.

A new polymer brush was synthesized by spontaneous polymerization of benzofulvene macromonomer 6-MOEG-9-T- bearing a nona(ethylene glycol) side chain linked to the 3-phenylindene scaffold by means of a triazole heterocycle. The polymer structure was studied by SEC-MALS, NMR spectroscopy, and MALDI-TOF MS techniques, and the results supported the role of oligomeric initiatory species in the spontaneous polymerization of polybenzofulvene derivatives. The aggregation features of high molecular weight poly-6-MOEG-9-T--FE were investigated by pyrene fluorescence analysis, dynamic light scattering studies, and transmission electron microscopy, which suggested a tendency towards the formation of spherical objects showing dimensions in the range of 20-200 nm. Moreover, poly-6-MOEG-9-T--FE showed an interesting cytocompatibility in the whole concentration range tested that, besides its aggregation features, makes this polybenzofulvene brush a good polymer candidate for nanoencapsulation and delivery of drug molecules. Finally, the photo-physical features of poly-6-MOEG-9-T--FE could allow the biodistribution of the resulting drug delivery systems to be monitored by fluorescence microscopy techniques.
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http://dx.doi.org/10.3390/pharmaceutics11090444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781277PMC
September 2019

Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold.

Bioorg Med Chem 2019 10 9;27(19):115045. Epub 2019 Aug 9.

Dipartimento di Biotecnologie, Chimica e Farmacia, (Dipartimento d'Eccellenza 2018-2022), Università di Siena, Via A. Moro, I-53100 Siena, Italy. Electronic address:

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.
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http://dx.doi.org/10.1016/j.bmc.2019.115045DOI Listing
October 2019

Structural Manipulation of the Conjugated Phenyl Moiety in 3-Phenylbenzofulvene Monomers: Effects on Spontaneous Polymerization.

Polymers (Basel) 2018 Jul 7;10(7). Epub 2018 Jul 7.

Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022), Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.

Spontaneous polymerization is an intriguing phenomenon in which pure monomers begin their polymerization without initiators or catalysts. Previously, 3-phenylbenzofulvene monomers were found to polymerize spontaneously after solvent removal. Here, eight new 3-substituted benzofulvene monomers were synthesized in order to investigate the effects of differently substituted aromatic rings in position 3 of the benzofulvene scaffold on spontaneous polymerization. The newly synthesized monomers maintained the tendency toward spontaneous polymerization. However, monomer , bearing an ortho-methoxy substituted phenyl, polymerized hardly, thus producing low polymerization yields, inhomogeneous structure, and low molecular weight of the obtained polymeric material. This result suggested the importance of the presence of hydrogen atoms in the 2'-position to achieve productive interactions among the monomers in the recognition step preluding the spontaneous polymerization and among the monomeric units in the polybenzofulvene backbones. Moreover, this study paves the way to modify the pendant rings in position 3 of the indene scaffold to synthesize new polybenzofulvene derivatives variously decorated.
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http://dx.doi.org/10.3390/polym10070752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403996PMC
July 2018

Densely PEGylated Polybenzofulvene Brushes for Potential Applications in Drug Encapsulation.

Pharmaceutics 2018 Nov 15;10(4). Epub 2018 Nov 15.

Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018⁻2022), Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The technique of grafting side chains onto a linear polymeric backbone is commonly used to confer to the new polymeric material with desired properties, such as tunable solubility, ionic charge, biocompatibility, or specific interactions with biological systems. In this paper, two new polybenzofulvene backbones were assembled by spontaneous polymerization of the appropriate benzofulvene monomers (4,6-PO- and 4',6-PO-) bearing two clickable propargyloxy groups in different positions of the 3-phenylindene scaffold. Poly-4,6-PO- and poly-4',6-PO- were grafted with monomethyl oligo(ethylene glycol) (MOEG) to prepare two new polybenzofulvene brushes (i.e., poly-4,6-MOEG-9-TM- and poly-4',6-MOEG-9-TM-) by means of a "grafting onto" approach, that were characterized from the point of view of their macromolecular features, aggregation liability, and in a preliminary evaluation of biocompatibility. The obtained results make these PEGylated polybenzofulvene brushes (PPBFB) derivatives potentially useful as nanocarriers for nanoencapsulation and delivery of drug molecules.
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http://dx.doi.org/10.3390/pharmaceutics10040234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321592PMC
November 2018

Development of subnanomolar-affinity serotonin 5-HT receptor ligands based on quinoline structures.

Medchemcomm 2018 Sep 3;9(9):1466-1471. Epub 2018 Jul 3.

Dipartimento di Biotecnologie , Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022) , Università degli Studi di Siena , Via A. Moro 2 , 53100 Siena , Italy . Email: ; ; Tel: +39 0577 234320.

Two small series of quinoline derivatives were designed starting from previously published quinoline derivatives and in order to obtain information about their interaction with the 5-HTR binding site. Initially, the structure of and was modified by replacing their basic moiety with that of partial agonist (ML10302) or with that of reference ligand (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates , , and or 4-quinolinecarboxamides , , and were modified into those of 2-quinolinecarboxamides . Very interestingly, this structure-affinity relationship study led to the discovery of as novel 5-HTR ligands showing values in the subnanomolar range. The structures of all these compounds contain the -butyl-4-piperidinylmethyl substituent, which appear to behave as an optimized basic moiety in the interaction of these 4-quinolinecarboxylates with the 5-HTR binding site. However, this basic moiety was ineffective in providing 5-HTR affinity in the corresponding 4-quinolinecarboxamide , but it did in 2-quinolinecarboxamide ligands . Thus, a subtle interrelationship of several structural parameters appeared to play a major role in the interaction of the ligands with the 5-HTR binding site. They include the kind of basic moiety, the position of the carbonyl linking group with respect to the aromatic moiety and its orientation, which could be affected by the presence of the intramolecular H-bond as in compounds .
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http://dx.doi.org/10.1039/c8md00233aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148519PMC
September 2018

The 5 MS Food Day Conference: Mass spectrometry applications in food analysis Bologna (Italy), October 11-13, 2017.

Authors:
Gianluca Giorgi

J Mass Spectrom 2018 Sep;53(9):741-742

Chairman of the 5th MS Food Day Scientific Committee, JMS Special Issue Editor.

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http://dx.doi.org/10.1002/jms.4276DOI Listing
September 2018

Nutraceutical potential of hemp (Cannabis sativa L.) seeds and sprouts.

Food Chem 2018 Oct 22;262:56-66. Epub 2018 Apr 22.

National Research Council (CNR), Institute of Agricultural Biology and Biotechnology (IBBA), Research Unit of Pisa, Via Moruzzi 1, 56124 Pisa, Italy. Electronic address:

In this study the antioxidant effect of Cannabis sativa L. seeds and sprouts (3 and 5 days of germination) was evaluated. Total polyphenols, flavonoids and flavonols content, when expressed on dry weight basis, were highest in sprouts; ORAC and DPPH (in vitro assays), CAA-RBC (cellular antioxidant activity in red blood cells) and hemolysis test (ex vivo assays) evidenced a good antioxidant activity higher in sprouts than in seeds. Untargeted analysis by high resolution mass spectrometry in negative ion mode allowed the identification of main polyphenols (caffeoyltyramine, cannabisin A, B, C) in seeds and of ω-6 (linoleic acid) in sprouts. Antimutagenic effect of seeds and sprouts extracts evidenced a significant decrease of mutagenesis induced by hydrogen peroxide in Saccharomyces cerevisiae D7 strain. In conclusion our results show that C. sativa seeds and sprouts exert beneficial effects on yeast and human cells and should be further investigated as a potential functional food.
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http://dx.doi.org/10.1016/j.foodchem.2018.04.078DOI Listing
October 2018

C24-hydroxylated stigmastane derivatives as Liver X Receptor agonists.

Chem Phys Lipids 2018 05 17;212:44-50. Epub 2018 Jan 17.

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo 1, 06123, Perugia, Italy. Electronic address:

Phytosterols are stucturally correlated to the endogenous ligands of Liver X Receptor (LXR), a ligand-activated nuclear receptor that has emerged as an attractive drug target due to its ability to integrate metabolic and inflammatory signaling. Natural and semi-synthetic phytosterol derivatives characterized by the presence of side-chain oxygenated functions have shown to be able to modulate LXR activity. Here, we describe the efficient synthesis of four stigmastane derivatives, endowed with a hydroxyl group at C24 position, namely (24R)- and (24S)-stigmasta-5,28-diene-3β,24-ols (also referred to as saringosterols, 10a and 10b) and (24R)- and (24S)-stigmasta-5-ene-3β,24-ols (11a and 11b), starting from the readily available stigmasterol. Thanks to X-ray crystallography the absolute configuration of the newly created chiral centers was definitively assigned for all the four compounds. The subsequent luciferase assays with GAL-4 chimeric receptors evidenced the ability of the two 24(S)-epimers, 10b and 11b, to interact with LXRs, showing the same degree of affinity as (22R)-hydroxycholesterol (1). With regard to the isoform selectivity both the derivatives 10b and 11b showed a preference for LXRβ, up to 4-fold in terms of efficacy for 11b. The gene expression profiling of (24S)-stigmasta-5,28-diene-3β,24-ol (10a) and (24S)-stigmasta-5-ene-3β,24-ol (11a) demonstrated the capability of both the compounds to induce the expression of four well-known LXR target genes, such as ABCA1, SREBP1c, FASN, and SCD1 in U937 monocytic cell line, thus supporting the hypothesis they were LXR positive modulators.
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http://dx.doi.org/10.1016/j.chemphyslip.2018.01.005DOI Listing
May 2018

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages.

ChemMedChem 2018 03 14;13(5):422-430. Epub 2018 Feb 14.

European Research Centre for Drug Discovery and Development - NatSynDrugs - and Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, via Aldo Moro 1, 53100, Siena, Italy.

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.
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http://dx.doi.org/10.1002/cmdc.201700759DOI Listing
March 2018

Screening and identification of major phytochemical compounds in seeds, sprouts and leaves of Tuscan black kale Brassica oleracea (L.) ssp acephala (DC) var. sabellica L.

Nat Prod Res 2018 Jul 23;32(14):1617-1626. Epub 2017 Oct 23.

a Institute of Agricultural Biology and Biotechnology , National Research Council (CNR) , Pisa , Italy.

We report the spectrophotometric determination of total polyphenols, flavonoids, glucosinolates and antioxidant activity in seeds, seedlings and leaves of Tuscan black kale. The highest content of phytochemicals was observed in 10 days sprouts and antioxidant activity was maximum in 2, 4 days seedlings. Identification and characterisation of phytochemicals were performed by mass spectrometry (MS), high resolution and tandem MS with electrospray ionisation mode. Low-molecular-weight metabolites were evidenced in seeds while metabolites at high m/z range were detected in cotyledons and leaves. MS spectra evidenced different phenolic compounds (flavonoid caffeoyl glucose, hydroxycinnamic acid sinapine) and glucosinolates (glucoerucin, glucobrassicin and glucoraphanin) in function of developmental stage; galactolipids ω3 and ω6 were observed in leaves. Identification of stages with the highest phytochemicals content encourages the consumption of black kale sprouts and young leaves. Our research can support food and pharmaceutical industries for production of health promoting products from black kale.
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http://dx.doi.org/10.1080/14786419.2017.1392953DOI Listing
July 2018

Divergent Approach to Thiazolylidene Derivatives: A Perspective on the Synthesis of a Heterocyclic Skeleton from β-Amidothioamides Reactivity.

J Org Chem 2017 09 5;82(18):9773-9778. Epub 2017 Sep 5.

Department of Biomolecular Sciences, Section of Organic Chemistry and Organic Natural Compounds, University of Urbino "Carlo Bo" , Via I Maggetti 24, 61029 Urbino, Italy.

Herein we report a domino protocol able to reach regioselectively thiazolylidene systems by combining the reactive peculiarities of both β-amidothioamides (ATAs) and 1,2-diaza-1,3-dienes (DDs). Depending on the reaction conditions and/or the nature of the residue at C4 of the heterodiene system, ATAs can act as hetero-mononucleophiles or hetero-dinucleophiles in the diversified thiazolylidene ring assembly.
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http://dx.doi.org/10.1021/acs.joc.7b02135DOI Listing
September 2017

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists.

J Med Chem 2017 08 25;60(15):6548-6562. Epub 2017 Jul 25.

Istituto Scientifico Ospedale San Raffaele (IRCCS) , Via Olgettina, 58-20132 Milano, Italy.

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00091DOI Listing
August 2017

Synthesis and Biological Evaluation of Novel Neuroprotective Pyridazine Derivatives as Excitatory Amino Acid Transporter 2 (EAAT2) Activators.

J Med Chem 2017 06 31;60(12):5216-5221. Epub 2017 May 31.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via A. Moro 2, 53100 Siena, Italy.

LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a-f) of EAAT2. Among them 4f, analyzed in comparison with 3 by different paradigms in a rat model of oxaliplatin-induced neuropathic pain, showed the better antihypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00383DOI Listing
June 2017

Synthesis and biological evaluation of a new class of benzothiazines as neuroprotective agents.

Eur J Med Chem 2017 Jan 27;126:614-630. Epub 2016 Nov 27.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy. Electronic address:

Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na and Ca-channels, showing a profile comparable with that of 1.
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http://dx.doi.org/10.1016/j.ejmech.2016.11.053DOI Listing
January 2017

Phenylindenone isomers as divergent modulators of p38α MAP kinase.

Bioorg Med Chem Lett 2016 11 4;26(21):5160-5163. Epub 2016 Oct 4.

Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.001DOI Listing
November 2016

Mechanistic study of competitive releases of HO, NH and CO from deprotonated aspartic and glutamic acids: Role of conformation.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Mar 24;1047:64-74. Epub 2016 Aug 24.

CEA, iBiTec-S, SPI, LEMM, Metabohub Gif Sur Yvette, France; Université Paris VI (UPMC), CNRS UMR 7201, Paris Cedex 05, France.

The aims of this study were to highlight the impact of minor structural differences (e.g. an aminoacid side chain enlargement by one methylene group), on ion dissociation under collision-induced dissociation conditions, and to determine the underlying chemical mechanisms. Therefore, we compared fragmentations of deprotonated aspartic and glutamic acids generated in negative electrospray ionization. Energy-resolved mass spectrometry breakdown curves were recorded and MS experiments performed on an Orbitrap Fusion for high-resolution and high-mass accuracy measurements. Activated fragmentations were performed using both the resonant and non-resonant excitation modes (i.e., CID and HCD, respectively) in order to get complementary information on the competitive and consecutive dissociative pathways. These experiments showed a specific loss of ammonia from the activated aspartate but not from the activated glutamate. We mainly focused on this specific observed loss from aspartate. Two different mechanisms based on intramolecular reactions (similar to those occurring in organic chemistry) were proposed, such as intramolecular elimination (i.e. Ei-like) and nucleophilic substitution (i.e. SNi-like) reactions, respectively, yielding anions as fumarate and α lactone from a particular conformation with the lowest steric hindrance (i.e. with antiperiplanar carboxyl groups). The detected deaminated aspartate anion can then release CO as observed in the MS experimental spectra. However, quantum calculations did not indicate the formation of such a deaminated aspartate product ion without loss of carbon dioxide. Actually, calculations displayed the double neutral (NH+CO) loss as a concomitant pathway (from a particular conformation) with relative high activation energy instead of a consecutive process. This disagreement is apparent since the concomitant pathway may be changed into consecutive dissociations according to the collision energy i.e., at higher collision energy and at lower excitation conditions, respectively. The latter takes place by stabilization of the deaminated aspartate solvated with two residual molecules of water (present in the collision cell). This desolvated anion formed is an α lactone substituted by a methylene carboxylate group. The vibrational excitation acquired by [(D-H)-NH]during its isolation is enough to allow its prompt decarboxylation with a barrier lower than 8.4kJ/mol. In addition, study of glutamic acid-like diastereomers constituted by a cyclopropane, hindering any side chain rotation, confirms the impact of the three-dimensional geometry on fragmentation pathways. A significant specific loss of water is only observed for one of these diastereomers. Other experiments, such as stable isotope labeling, need to be performed to elucidate all the observed losses from activated aspartate and glutamate anions. These first mechanistic interpretations enhance understanding of this dissociative pathway and underline the necessity of studying fragmentation of a large number of various compounds to implement properly new algorithms for de novo elucidation of unknown metabolites.
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http://dx.doi.org/10.1016/j.jchromb.2016.08.036DOI Listing
March 2017

Anti-Selective Organocatalytic Michael Addition between Phenylacetaldehyde and Nitrostyrene.

J Org Chem 2016 09 1;81(17):7952-7. Epub 2016 Aug 1.

Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology , Buenos Aires, Argentina.

Using the reaction between phenylacetaldehyde and nitrostyrene catalyzed by pyrrolidine as a simple model, we have studied the diastereochemical outcome of the organocatalytic Michael reactions between benzylic aldehydes and nitrostyrenes. We found that the anti adduct was obtained in high yield and diastereoselection as was demonstrated by the X-ray structure of the product. In situ NMR studies showed a different reaction pathway when compared to aliphatic aldehydes that yield the syn adduct as major isomer.
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http://dx.doi.org/10.1021/acs.joc.6b01061DOI Listing
September 2016

Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors.

J Med Chem 2016 Apr 24;59(7):3353-72. Epub 2016 Mar 24.

Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Cittadella Universitaria , S.S. 554-Km 4.500, 09042 Monserrato Cagliari, Italy.

A series of imidazo[1,5-a]quinoline derivatives was designed and synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high CBR affinity with Ki values within the submicromolar and subnanomolar ranges with interesting modulations in their structure-affinity relationships. In particular, fluoroderivative 7w (Ki = 0.44 nM) resulted in the most potent ligand among the imidazo[1,5-a]quinoline derivatives described so far. Overall, these observations confirmed the assumption concerning the presence of a large though apparently saturable lipophilic pocket in the CBR binding site region interacting with positions 4 and 5 of the imidazo[1,5-a]quinoline nucleus. The in vivo biological characterization revealed that compounds 7a,c,d,l,m,q,r,w show anxiolytic and antiamnestic activities without the unpleasant myorelaxant side effects of the classical 1,4-BDZ. Furthermore, the effect of 7l,q,r, and 8i in lowering lactate dehydrogenase (LDH) release induced by ischemia-like conditions in rat brain slices suggested neuroprotective properties for these imidazo[1,5-a]quinoline derivatives.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00034DOI Listing
April 2016

Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity.

Eur J Med Chem 2016 Feb 28;109:99-106. Epub 2015 Dec 28.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address:

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described.
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http://dx.doi.org/10.1016/j.ejmech.2015.12.044DOI Listing
February 2016

Correction: Wound healing properties of hyaluronan derivatives bearing ferulate residues.

J Mater Chem B 2015 Sep 20;3(36):7307. Epub 2015 Aug 20.

Dipartimento di Scienze della Vita e Biotecnologie, Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

Correction for 'Wound healing properties of hyaluronan derivatives bearing ferulate residues' by Giuseppe Valacchi et al., J. Mater. Chem. B, 2015, DOI: .
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http://dx.doi.org/10.1039/c5tb90126jDOI Listing
September 2015
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