Publications by authors named "Antonella Di Stilo"

27 Publications

  • Page 1 of 1

Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation.

Circ Res 2018 01 20;122(1):31-46. Epub 2017 Nov 20.

From the Goethe University, Frankfurt am Main, Germany (F. Spallotta, C.C., S.A., S.Z., D.S., F. Schnütgen, H.v.M., A.F., I.F., A.M.Z., C.G.); University of Turin, Torino, Italy (D.G., M. Cocco, R.M., A.D.S., M.A., M. Collino, M. Bertinaria); Istituto Italiano di Tecnologia CLNS@Sapienza Rome, Italy (M.M.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (C.K., S.G., T.B.); Università Cattolica del Sacro Cuore, Rome, Italy (S.N.); Karolinska Institutet, Huddinge, Sweden (V.A.); University of Mainz, Germany (A.K., A.B.-F.); NXT-Dx, Ghent, Belgium (M. Braspenning); Ghent University, Belgium (W.v.C.); Baker IDI Heart and Diabetes Institute, Melbourne VIC, Australia (M.J.D.B., R.H.R.); IRCCS Policlinico San Donato, Milan, Italy (G.Z., F.M.); National Research Council, Rome, Italy (A.F., C.C.); and Sapienza University, Rome, Italy (B.B.).

Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.

Objective: To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.

Methods And Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten-eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.

Conclusions: Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311300DOI Listing
January 2018

New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity.

Eur J Pharm Sci 2015 May 10;72:69-80. Epub 2015 Mar 10.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address:

A number of new nitric oxide (NO)-precursors were synthesized by grafting nitrate-containing moieties on the structures of the benzyloxy isonipecotanilide derivatives 1 and 2 already reported as moderately potent antiplatelet agents. Various nitrooxy (ONO2)-alkyl side chains were covalently linked to the piperidine nitrogen of the parent compounds through carbamate and amide linkage, and the synthesis of a benzyl nitrate analog (15) of compound 1 was also achieved. The in vitro vasodilatory activities, as well as platelet anti-aggregatory effects, of the newly synthesized organic nitrates were assessed. The (ONO2)methyl carbamate-based derivative 5a and the benzyl nitrate analog 15, which on the other hand retain activity as inhibitors of ADP-induced platelet aggregation, exhibited strong NO-mediated vasodilatory effects on pre-contracted rat aorta strips, with EC50 values in the low nanomolar range (13 and 29 nM, respectively). Experiments carried out with the selectively inhibited soluble guanylate cyclase (sGC), which is the key enzyme of the NO-mediated pathway leading to vascular smooth muscle relaxation, confirmed the involvement of NO in the observed vasodilation. The nitrate derivatives proved to be stable in acidic aqueous solution and at pH 7.4. In human serum, unlike 5a, which showed not to undergo enzyme-catalyzed decomposition, the other tested (ONO2)-alkyl carbamate-based compounds (5b and 5e) and benzyl nitrate 15 underwent a faster degradation. However, their decomposition rates in serum were quite slow (t½>2.6 h), which suggests that nitrate moiety is poorly metabolized in blood plasma and that much of the in vitro anti-platelet activity has to be attributed to the intact (ONO2)-containing molecules.
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http://dx.doi.org/10.1016/j.ejps.2015.03.004DOI Listing
May 2015

Simultaneous ultrasound-assisted water extraction and β-cyclodextrin encapsulation of polyphenols from Mangifera indica stem bark in counteracting TNFα-induced endothelial dysfunction.

Nat Prod Res 2015 15;29(17):1657-63. Epub 2015 Jan 15.

a Vascular and Endovascular Surgery Unit, Research Laboratory of Experimental and Clinical Vascular Biology, DISC , University of Genoa , IRCCS San Martino - IST, 16132 Genoa , Italy.

This study proposes an alternative technique to prevent heat degradation induced by classic procedures of bioactive compound extraction, comparing classical maceration/decoction in hot water of polyphenols from Mango (Mangifera indica L.) (MI) with ultrasound-assisted extraction (UAE) in a water solution of β-cyclodextrin (β-CD) at room temperature and testing their biological activity on TNFα-induced endothelial dysfunction. Both extracts counteracted TNFα effects on EAhy926 cells, down-modulating interleukin-6, interleukin-8, cyclooxygenase-2 and intracellular adhesion molecule-1, while increasing endothelial nitric oxide synthase levels. β-CD extract showed higher efficacy in improving endothelial function. These effects were abolished after pre-treatment with the oestrogen receptor inhibitor ICI1182,780. Moreover, the β-CD extract induced Akt activation and completely abolished the TNFα-induced p38MAPK phosphorylation. UAE and β-CD encapsulation provide an efficient extraction protocol that increases polyphenol bioavailability. Polyphenols from MI play a protective role on endothelial cells and may be further considered as oestrogen-like molecules with vascular protective properties.
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http://dx.doi.org/10.1080/14786419.2014.996753DOI Listing
October 2015

Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.

J Med Chem 2014 Dec 4;57(24):10366-82. Epub 2014 Dec 4.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via P. Giuria 9, 10125 Torino, Italy.

Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure-activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.
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http://dx.doi.org/10.1021/jm501072bDOI Listing
December 2014

A lipophilic nitric oxide donor and a lipophilic antioxidant compound protect rat heart against ischemia-reperfusion injury if given as hybrid molecule but not as a mixture.

J Cardiovasc Pharmacol 2012 Mar;59(3):241-8

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 μM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.
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http://dx.doi.org/10.1097/FJC.0b013e31823d2dcaDOI Listing
March 2012

New nitric oxide or hydrogen sulfide releasing aspirins.

J Med Chem 2011 Aug 6;54(15):5478-84. Epub 2011 Jul 6.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.

A new series of (((R-oxy)carbonyl)oxy)methyl esters of aspirin (ASA), bearing nitric oxide (NO) or hydrogen sulfide (H(2)S) releasing groups, was synthesized, and the compounds were evaluated as new ASA co-drugs. All the products were quite stable in buffered solution at pH 1 and 7.4. Conversely, they were all rapidly metabolized, producing ASA and the NO/H(2)S releasing moiety used for their preparation. Consequent on ASA release, the compounds were capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma (PRP). The simple NO/H(2)S donor substructures were able to relax contracted rat aorta strips, with a NO- and H(2)S-dependent mechanism, respectively, but they either did not trigger antiaggregatory activity or displayed antiplatelet potency markedly below that of the related co-drug. The new products might provide a safer and improved alternative to the use of ASA principally in its anti-inflammatory and antithrombotic applications.
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http://dx.doi.org/10.1021/jm2004514DOI Listing
August 2011

(Nitrooxyacyloxy)methyl esters of aspirin as novel nitric oxide releasing aspirins.

J Med Chem 2009 Aug;52(16):5058-68

Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.
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http://dx.doi.org/10.1021/jm900587hDOI Listing
August 2009

Nitrooxymethyl-substituted analogues of rofecoxib: synthesis and pharmacological characterization.

Chem Biodivers 2010 May;7(5):1173-82

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, I-10125 Torino.

Nitrooxymethyl-substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet-rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti-aggregatory properties, are closely dependent on the position at which the NO-donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose-dependent manner, through a cGMP-dependent mechanism. Compound 10 emerged as a quite potent COX-2-selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX-1 inhibitor, and displayed good vasodilator and anti-aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.
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http://dx.doi.org/10.1002/cbdv.200900421DOI Listing
May 2010

Physicochemical profile and in vitro permeation behavior of a new class of non-steroidal anti-inflammatory drug candidates.

Eur J Pharm Sci 2010 Jun 25;40(3):217-21. Epub 2010 Mar 25.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

Recently a new series of nitrooxy-acyl derivatives of salicylic acid (SA) was described presenting similar anti-inflammatory activities but reduced or no gastrotoxicity compared to aspirin. In this work, lipophilicity and permeability profiles of SA derivatives were performed to evaluate their ADME properties related to oral or transdermic delivery. All tested compounds showed potential good passive permeation through gastrointestinal track and also through percutaneous barrier which could be a way to avoid the first hepatic pass.
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http://dx.doi.org/10.1016/j.ejps.2010.03.015DOI Listing
June 2010

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs).

Bioorg Med Chem 2010 Apr 1;18(7):2428-38. Epub 2010 Mar 1.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK(a) values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10microM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.
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http://dx.doi.org/10.1016/j.bmc.2010.02.058DOI Listing
April 2010

Synthesis of some novel organic nitrates and comparative in vitro study of their vasodilator profile.

J Med Chem 2009 Jul;52(13):4020-5

Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, 10125 Torino, Italy.

Synthesis and structural characterization of the 4-phenylbutane-1,2-diyl dinitrate and of the erythro and threo diastereoisomers of 4-phenylbutane-1,2,3-triyl trinitrate as well as the HPLC chiral separation of the corresponding racemic mixtures are reported. Vasodilator activity of the single enantiomers of these products, of 4-phenylbutyl nitrate, and of the previously described phenylpropyl analogues were assessed on rat aorta strips precontracted with phenylephrine. The compounds were able to relax the contracted tissue in a concentration dependent manner. In the couples of antipodes, a complete lack of enantioselectivity was observed as far as the vasodilator potency is concerned. The concentration response curves of the products, with the exception of those of all the trinitrooxy substituted models, were rightward shifted in the presence of ALDH-2 inhibitors. Mono and dinitrates, but not trinitrates, displayed in vitro cross-tolerance with GTN. This new series of nitric acid esters is an interesting tool that can help to shed light on the unresolved puzzle of nitrate pharmacology. Selected members are worthy of additional study as potential drugs.
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http://dx.doi.org/10.1021/jm9002236DOI Listing
July 2009

Effects of nitric oxide donor antioxidants containing the phenol vitamin E substructure and a furoxan moiety on ischemia/reperfusion injury.

Arzneimittelforschung 2009 ;59(3):111-6

Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, Italy.

Nitric oxide (NO) donor antioxidants are a class of polyvalent drugs which is the focus of great interest today. They are potentially useful for the treatment of many forms of cardiovascular diseases, including the myocardial ischemia/reperfusion (I/R) damage which seems to be due to both a burst of reactive oxygen species (ROS) and a reduced release of NO during reperfusion. In this paper the results of a study on the ability of new NO-donor antioxidants containing the phenol vitamin E substructure and furoxan moiety to attenuate I/R damage are reported. The compounds under study are obtained by combining the phenol moiety (6-hydroxy-2,2,5,7,8-pentamethylchroman) present in vitamin E with differently substituted furoxan substructures endowed with different capacity of NO-release. Their antioxidant and NO-dependent vasodilator activities are reported. The I/R experiments were performed on isolated rat heart preparations perfused at a constant flow. After 20 min of stabilization, global ischemia was obtained by interrupting the perfusion for 30 min. After ischemia the hearts were reperfused for 2 h. The compounds were added to the perfusion buffer during the first 20 min of reperfusion. At the end of each experiment, the infarct size was measured with nitro-blue tetrazolium. From the results it appears that the limitation of the infarct area is favoured by an appropriate balance between NO-donor and antioxidant properties and that these two actions are synergic.
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http://dx.doi.org/10.1055/s-0031-1296372DOI Listing
June 2009

Nitrooxymethyl-substituted analogues of celecoxib: synthesis and pharmacological characterization.

Chem Biodivers 2009 Mar;6(3):369-79

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, Turin.

Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.
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http://dx.doi.org/10.1002/cbdv.200800307DOI Listing
March 2009

Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

J Med Chem 2007 Oct 11;50(20):5003-11. Epub 2007 Sep 11.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol.
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http://dx.doi.org/10.1021/jm0704595DOI Listing
October 2007

High-speed gas chromatography in doping control: fast-GC and fast-GC/MS determination of beta-adrenoceptor ligands and diuretics.

J Sep Sci 2006 Dec;29(18):2765-71

Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Italy.

In official doping controls, about 300 drugs and metabolites have to be screened for each sample. Moreover, the number of determinations to be routinely processed increases continuously as the number of both samples and potential illicit drugs keeps growing. As a consequence, increasingly specific, sensitive, and, above all, fast methods for doping controls are needed. The present study presents an efficient fast-GC/MS approach to the routine screening of two different classes of doping agents, namely beta-adrenoceptor ligands and diuretics (belonging to the S3, P2, and S5 groups of the WADA list of prohibited substances). Narrow bore columns (100 mm id) of different lengths and coated with apolar stationary phases were successfully used to separate the derivatized analytes; preliminary experiments (results not shown) showed better performances with OV-1701 for the separation of beta-adrenoceptor ligands. On the same stationary phase some diuretics required too high a temperature or a long isothermal time for elution, in which case a DB1-MS column was preferred. Two methods of sample preparation, derivatization, and analysis were used on aqueous standard mixtures of, respectively, (i) eight beta-adrenoceptor ligands, including five beta-antagonists (acebutolol, alprenolol, atenolol, metoprolol, pindolol) and three beta2-agonists (salbutamol, clenbuterol, terbutaline) and (ii) seventeen diuretic drugs (acetazolamide, althiazide, bendroflumethiazide, bumethanide, canrenone, chlorothiazide, chlortalidone, clopamide, ethacrinic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, indomethacine, spironolactone, triamterene, trichloromethiazide) and one masking agent (probenecid). The mixture of beta-adrenoceptor ligand derivatives was efficiently separated in about 5.6 min, while the one of 18 diuretics and masking agents required less than 5 min for analysis. Limits of detection were from 1 microg/L for pindolol, ethacrinic acid, furosemide, indomethacine, and trichloromethiazide, to 20 microg/L for terbutaline, salbutamol, and metoprolol, and 50 microg/L for clopamide; the instrumental repeatability proved to be excellent (area RSD% <2 for almost all analytes). For this work a quadrupole MS with inert ion source has been used, demonstrating that the quadrupole technology is perfectly adequate to provide precise integration of 400 ms-wide GC peaks.
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http://dx.doi.org/10.1002/jssc.200500387DOI Listing
December 2006

The furoxan system: design of selective nitric oxide (NO) donor inhibitors of COX-2 endowed with anti-aggregatory and vasodilating activities.

Chem Biodivers 2005 Jul;2(7):886-900

Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy.

Several NO donor 3,4-diphenylfuroxan (= 3,4-diphenyl-1,2,5-oxadiazole 2-oxide) derivatives were synthesized and tested for their COX-inhibiting activities. The products were found to be selective COX-2 inhibitors, similar to the structurally related furazans (3,4-diphenyl-1,2,5-oxadiazole), devoid of the NO release property. This behavior was confirmed by a molecular-docking study. The NO-dependent platelet anti-aggregatory and vasodilating activities of the new furoxans 5-7 were studied in vitro. These properties can be modulated by inserting an appropriate spacer between the 4-phenyl group and the furoxan ring, giving rise to new, selective COX-2 furoxan derivatives endowed with anti-aggregatory and vasodilating activities, and with potentially reduced cardiotoxicities.
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http://dx.doi.org/10.1002/cbdv.200590065DOI Listing
July 2005

Amphiphilic NO-donor antioxidants.

ChemMedChem 2007 Feb;2(2):234-40

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

Models of amphiphilic NO-donor antioxidants 24-26 were designed and synthesized. The products were obtained by linking a lipophilic tail (C(6), C(8), C(10)) with a polar head constituted by the 2,6-dimethoxyphenol antioxidant joined to the NO-donor 3-furoxancarboxamide substructure through a bridge containing a quaternary ammonium group. Compound 23, containing the shortest C(2)-alkyl chain, was also studied as a reference. The antioxidant properties (TBARS and LDL oxidation assays) and the vasodilator properties of the compounds were studied in vitro. The ability of these products to interact with phospholipid vesicles was also investigated by NMR techniques. The results indicate that both activities are modulated by the ability of the compounds to accumulate on phospholipid layers.
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http://dx.doi.org/10.1002/cmdc.200600248DOI Listing
February 2007

NO-donor phenols: a new class of products endowed with antioxidant and vasodilator properties.

J Med Chem 2006 May;49(10):2886-97

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

The synthesis and study of the antioxidant and vasodilator properties of a new class of phenols able to release nitric oxide are described. The products were designed through a symbiotic approach using selected phenols and selected nitrooxy and furoxan NO-donors as reference models. The antioxidant activities of the hybrid products were assessed by detecting the 2-thiobarbituric acid reactive substances (TBARS) produced in the ferrous salt/ascorbate-induced autoxidation of lipids present in microsomial membranes of rat hepatocytes. The vasodilator activity was assessed on rat aortic strips precontracted with phenylephrine. Some of the products (13, 35, 37, 60-62, 64) behave principally as vasodilators and others as antioxidants (24, 32, 72), and the two properties are relatively balanced in 19, 41, and 68. Further in vivo studies should clarify whether some of these products may become preclinical candidates for the treatment of cardiovascular disease underpinned by atheroma.
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http://dx.doi.org/10.1021/jm0510530DOI Listing
May 2006

Synthesis, chiral HPLC resolution and configuration assignment of 1-phenylglyceryl trinitrate stereomers.

Chirality 2006 Jun;18(6):430-6

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.

As an introductory study of in vitro vasodilating activity, the access to the four stereomers of 1-phenylglyceryl trinitrate is described using achiral and chiral chromatography. For semi-preparative separation of the enantiomers, a Chiralcel OD (250 x 10 mm, 10 microm) was used. Catalytic reduction leading to the corresponding stereomers of 1-phenylglycerol allowed absolute configuration assignments. The same methods were used for the separation and configuration assignment of the enantiomers of 3-phenylpropane-1,2-diyl dinitrate.
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http://dx.doi.org/10.1002/chir.20278DOI Listing
June 2006

Furoxan analogues of the histamine H3-receptor antagonist imoproxifan and related furazan derivatives.

Bioorg Med Chem 2005 Aug;13(15):4750-9

Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125 Torino, Italy.

Synthesis and pharmacological characterisation of a series of compounds in which the oxime substructure present in imoproxifan was constrained in the pentatomic NO-donor furoxan ring, as well as their structurally related furazan analogues devoid of NO-donating properties, are described. The whole series of products displayed reversible histamine H3-antagonistic activity on guinea-pig ileum. 4-(4-(3-(1H-Imidazol-4-yl)propoxy)phenyl)furoxan-3-carbonitrile 16 was also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of its H3-antagonistic properties. This phenomenon seems to be dependent on NO-mediated sGC activation. The lipophilic-hydrophilic balance of all the products was investigated.
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http://dx.doi.org/10.1016/j.bmc.2005.05.004DOI Listing
August 2005

Non-imidazole histamine NO-donor H3-antagonists.

Farmaco 2005 Jun-Jul;60(6-7):507-12

Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125 Torino, Italy.

Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.
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http://dx.doi.org/10.1016/j.farmac.2005.04.007DOI Listing
June 2006

Development of a new class of potential antiatherosclerosis agents: NO-donor antioxidants.

Bioorg Med Chem Lett 2004 Dec;14(24):5971-4

Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125 Torino, Italy.

A new class of NO-donor phenol derivatives is described. The products were obtained by joining appropriate phenols with either nitrooxy or 3-phenylsulfonylfuroxan-4-yloxy moieties. All the compounds proved to inhibit the ferrous salt/ascorbate induced lipidic peroxidation of membrane lipids of rat hepatocytes. They were also capable of dilating rat aorta strips precontracted with phenylephrine.
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http://dx.doi.org/10.1016/j.bmcl.2004.10.006DOI Listing
December 2004

A new class of NO-donor H3-antagonists.

Farmaco 2004 May;59(5):359-71

Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, 10125 Torino, Italy.

Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 microM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.
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http://dx.doi.org/10.1016/j.farmac.2003.12.008DOI Listing
May 2004

New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

J Med Chem 2004 May;47(10):2688-93

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, I-10125 Torino, Italy.

A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.
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http://dx.doi.org/10.1021/jm031109vDOI Listing
May 2004

New potential uroselective NO-donor alpha1-antagonists.

J Med Chem 2003 Aug;46(17):3762-5

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Turin, Italy.

A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.
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http://dx.doi.org/10.1021/jm030825uDOI Listing
August 2003

[3-(1H-imidazol-4-yl)propyl]guanidines containing furoxan moieties: a new class of H3-antagonists endowed with NO-donor properties.

Bioorg Med Chem 2003 Apr;11(7):1197-205

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, I-10125 Turin, Italy.

Synthesis and pharmacological characterisation of a series of products obtained by coupling the H(3)-antagonist SKF 91486 through appropriate spacers with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan substructures, devoid of NO-donating properties, are reported. All the products were tested for their H(3)-antagonistic and H(2)-agonistic properties on electrically-stimulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. The whole series of compounds displayed good H(3)-antagonist behaviour and feeble partial H(2)-agonist activity. Among furoxan derivatives, the benzenesulfonyl hybrid 28, a good NO-donor, triggered a dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig intestine.
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http://dx.doi.org/10.1016/s0968-0896(02)00651-xDOI Listing
April 2003