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Ammazzalorso A Giancristofaro A D'Angelo A Filippis BD Fantacuzzi M Giampietro L Maccallini C Amoroso R 《Bioorganic & medicinal chemistry letters》2011,21(16):4869-4872
The discovery of PPAR antagonists is emerging as an useful tool for elucidating the biological role of the receptor. Here we report the identification of N-(phenylsulfonyl)amides containing the benzothiazole scaffold, a novel class of potent PPARα antagonists obtained from chemical modification of carboxylic acid agonists. In this work, a group of phenylsulfonamides were synthesized and in vitro evaluated against the agonistic effect of GW7647; they showed an inhibitory effect on PPARα activation, with best compounds revealing a dose-dependent antagonistic profile. Some of these antagonists showed also an inhibitory effect on CPT1A pattern expression. 相似文献
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Mangiacapra P Raimondo M Tammaro L Vittoria V Malinconico M Laurienzo P 《Biomacromolecules》2007,8(3):773-779
Polycaprolactone (PCL) was chemically modified by grafting maleic anhydride on it, through a radical reaction induced by benzoyl peroxide as initiator. To improve the grafting degree, a second unsaturated comonomer such as glycidyl methacrylate (GMA) has been added, demonstrating a good reactivity in melt grafting without leading to long grafted chains. The quantitative determination of grafted maleic anhydride, performed by FTIR analysis, revealed a grafting weight percentage of 9.5 +/- 0.9, and the NMR characterization made it possible to propose a structure for the grafted polymer (PCLgMA). The modified polymer was analyzed by DSC and X-ray diffraction, showing a structural organization even better than that of the pristine polymer. An exchange reaction with a layered double hydroxide (LDH), hydrotalcite-like solid in the nitrate form, led to the disappearance of the crystalline basal peak of LDH in the X-ray diffractograms, suggesting a possible exfoliation of the inorganic sample. An oxidative etching on the composite surface followed by atomic force microscopy analysis made it possible to enlighten the lamellar structure in the pristine sample. In the composite sample, the well identifiable narrow fissures homogeneously distributed on the surface demonstrate that nanometer stacks of LDH sheets, embedded in a highly textured PCLgMA matrix, are present in the composite sample. The comparison of X-ray diffractograms and AFM analysis suggests either a partial exfoliation or an intercalation of the polymer in a lamellar texture with a basal spacing higher than 5 nm. In any case, the process of ionic exchange between nitrate LDH and PCLgMA led to the formation of nanocomposites, in which no large hydrotalcite aggregates are present. This is an interesting method to obtain a direct intercalation of the modified polymer into the inorganic solid with a simple ionic exchange reaction. 相似文献
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Maccallini C Patruno A Lannutti F Ammazzalorso A De Filippis B Fantacuzzi M Franceschelli S Giampietro L Masella S Felaco M Re N Amoroso R 《Bioorganic & medicinal chemistry letters》2010,20(22):6495-6499
A series of N-substituted acetamidines and 2-methylimidazole derivatives structurally related to W1400 were synthesized and evaluated as Nitric Oxide Synthase (NOS) inhibitors. Analogs with sterically hindering isopropyl and phenyl substituents on the benzylic carbon connecting the aromatic core of W1400 to the acetamidine nitrogen, showed good inhibitory potency for nNOS (IC(50)=0.2 and 0.3 μM) and selectivity over eNOS (500 and 1166) and to a lesser extent over iNOS (50 and 100). A molecular modeling study allowed to shed light on the effects of the structural modifications on the selectivity of the designed inhibitors toward the different NOS isoforms. 相似文献
4.
Antonia Patruno Sara Franceschelli Mirko Pesce Cristina Maccallini Marialuigia Fantacuzzi Lorenza Speranza Alessio Ferrone Maria Anna De Lutiis Emanuela Ricciotti Rosa Amoroso Mario Felaco 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Previous reports suggest that NO may contribute to the pathophysiology of septic shock. Recently, we have synthesized and characterized a series of benzyl- and dibenzyl derivative of N-(3-aminobenzyl)acetamidine, a potent and selective inhibitor of iNOS, in vitro assay. We evaluated the molecular mechanisms by which these compounds are involved in the regulation of NOSs expression.Methods
H9c2 cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of acetamidine-derivative. The NOSs mRNA and protein, and activation of signaling pathways (Akt and NF-κB) were assayed.Results
The induction of endotoxic shock in H9c2 with LPS caused an increase of inducible NOS and a down-regulation of constitutive NOS. The molecular mechanism involved in the modulation of NOSs expression in H9c2 cells upon LPS stimulation resulted in the modification of the redox state responsible for NF-kB nuclear translocation via NIK -IKKα/β-IkBα, simultaneously to the inactivation of the PI3K/Akt pathway. The compounds acted as an anti-inflammatory modulator.Conclusion
These results suggest that LPS regulates the opposite NOS expression in H9c2 cells by modifying the redox state of these cells responsible for the NF-kB nuclear translocation via NIK–IKKα/β‐IkBα, simultaneous to the inactivation of the PI3K/Akt pathway. The new molecule acts as an anti-inflammatory modulator in LPS-induced inflammation in H9c2 cells by the restoration of eNOS and nNOS expressions, mechanistically involving the PI3K/Akt pathway.General significance
This study delineates the underlying mechanisms of opposite NOSs expression in H9c2 cells stimulated with LPS. 相似文献5.
Ammazzalorso A Amoroso R Bettoni G De Filippis B Fantacuzzi M Giampietro L Maccallini C Tricca ML 《Chirality》2008,20(2):115-118
Candida rugosa lipase-catalysed hydrolysis of three different 2-substituted-aryloxyacetic esters was performed in aqueous buffer containing dimethyl sulphoxide and isopropanol from 0 to 80% v/v as additives, in order to obtain an enhancement of the enantioselectivity. For 2-(p-chlorophenoxy)acetic acid and 2-n-butyl-2-(p-chlorophenoxy)acetic acid ethyl esters, DMSO enhanced enzyme enantioselectivity more than IPA with an opposite enzymatic enantiopreference. The cosolvents moderately improved Candida rugosa lipase enantioselectivity for 2-phenyl-2-(p-chlorophenoxy)acetic acid ethyl ester. 相似文献
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Alessandra Ammazzalorso Laura De Lellis Rosalba Florio Antonio Laghezza Barbara De Filippis Marialuigia Fantacuzzi Letizia Giampietro Cristina Maccallini Paolo Tortorella Serena Veschi Fulvio Loiodice Alessandro Cama Rosa Amoroso 《Bioorganic & medicinal chemistry letters》2019,29(16):2302-2306
The reduced activation of PPARs has a positive impact on cancer cell growth and viability in multiple preclinical tumor models, suggesting a new therapeutic potential for PPAR antagonists. In the present study, the benzothiazole amides 2a-g were synthesized and their activities on PPARs were investigated. Transactivation assay showed a moderate activity of the novel compounds as PPARα antagonists. Notably, in cellular assays they exhibited cytotoxicity in pancreatic, colorectal and paraganglioma cancer cells overexpressing PPARα. In particular, compound 2b showed the most remarkable inhibition of viability (greater than 90%) in two paraganglioma cell lines, with IC50 values in the low micromolar range. In addition, 2b markedly impaired colony formation capacity in the same cells. Taken together, these results show a relevant anti-proliferative potential of compound 2b, which appears particularly effective in paraganglioma, a rare tumor poorly responsive to chemotherapy. 相似文献
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Letizia Giampietro Alessandra D’Angelo Antonella Giancristofaro Alessandra Ammazzalorso Barbara De Filippis Marialuigia Fantacuzzi Pasquale Linciano Cristina Maccallini Rosa Amoroso 《Bioorganic & medicinal chemistry letters》2012,22(24):7662-7666
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ. 相似文献
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