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•Design, synthesis and biological evaluation of novel COX-2 selective inhibitors.•COX-2 inhibitors are efficacious as analgesic agents in vivo.•In silico studies highlight the binding ...mode of the compounds into COX-2 enzyme.
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.
An easy and viable crosslinking technology, based on the "click-chemistry" reaction copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (click-crosslinking), was applied to graft copolymers of ...medium molecular weight (i.e., 270 kDa) hyaluronic acid (
) grafted with ferulic acid (
) residues bearing clickable propargyl groups, as well as caffeic acid derivatives bearing azido-terminated oligo(ethylene glycol) side chains. The obtained crosslinked materials were characterized from the point of view of their structure and aggregation liability to form hydrogels in a water environment. The most promising materials showed interesting loading capability regarding the antioxidant agent phycocyanin (PC). Two novel materials complexes (namely
and
) were obtained with a drug-to-material ratio of 1:2 (
/
). Zeta potential measurements of the new complexes (-1.23 mV for
and -1.73 mV for
) showed alterations compared to the zeta potential values of the materials on their own, suggesting the achievement of drug-material interactions. According to the in vitro dissolution studies carried out in different conditions, novel drug delivery systems (DDSs) were obtained with a variety of characteristics depending on the desired route of administration and, consequently, on the pH of the surrounding environment, thanks to the complexation of phycocyanin with these two new crosslinked materials. Both complexes showed excellent potential for providing a controlled/prolonged release of the active pharmaceutical ingredient (API). They also increased the amount of drug that reach the target location, enabling pH-dependent release. Importantly, as demonstrated by the DPPH free radical scavenging assay, the complexation process, involving freezing and freeze-drying, showed no adverse effects on the antioxidant activity of phycocyanin. This activity was preserved in the two novel materials and followed a concentration-dependent pattern similar to pure PC.
New graft copolymers were prepared by reaction of poly (vinyl alcohol) (PVA) with mono-imidazolide or bis-imidazolide derivatives of ferulic acid (FA) with the formation of ester bonds. The obtained ...graft copolymers, thanks to the crosslinking capability of FA, formed in water strong gels as verified by rheological analyses. The resulting hydrogels were characterized to evaluate their applicability as wound dressing. In this perspective, their capability to absorb and retain a large amount of fluid without dissolving was verified by swelling kinetics and Moisture Vapour Transmission Rate measurements. Their stability towards mechanical solicitations was assessed by quantifying elasticity, compliance, stress-relaxation, and adhesivity properties. The analyses pointed out that hydrogel PVA-FA2-3 obtained by feruloylation of PVA with bis-imidazole derivative of ferulic acid using an acylation agent/polymer molar ratio 0.03/1 resulted the best candidate for the foreseen application.
An easy and viable crosslinking procedure by click-chemistry (click-crosslinking) of hyaluronic acid (
) was developed. In particular, the clickable propargyl groups of hyaluronane-based
-
-
graft ...copolymers showing low and medium molecular weight values were exploited in crosslinking by click-chemistry by using a hexa(ethylene glycol) spacer. The resulting
materials showed an apparent lack of in vitro cytotoxic effects, tuneable water affinity, and rheological properties according to the crosslinking degree that suggests their applicability in different biomedical fields.
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.
Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. ...For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole, was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37–148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.
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.
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.
The synthesis of a series of benzofulvene derivatives 3 related to the recently studied ethyl 1-methylene-3-(4-methylphenyl)-1H-indene-2-carboxylate (BF1) is described. The properties of these ...trans-diene derivatives were characterized with regard to their capability of polymerizing spontaneously to give new polymers based on functionalized indene monomeric units. The series of polymers has been investigated by NMR spectroscopy, multiangle light scattering online to size exclusion chromatography, UV−vis spectroscopy, mass spectrometry, differential scanning calorimetry, and scanning electron microscopy. The new polymers show very interesting properties such as a thermoreversible polymerization/depolymerization, a variable degree of π-stacking, a tendency to give nanostructured macromolecular aggregates, and a high solubility in the most common organic solvents. Remarkably, this study demonstrated that most of the polymer properties (e.g. formation, molecular weight, structure, thermoreversibility, and aggregation in nanostructured entities) may be modulated by the stereoelectronic characteristics of the substituents present on the indene moiety.
In order to obtain new fluorophores potentially useful in imidazole labeling and subsequent conjugation, a small series of Morita–Baylis–Hillman acetates (3a–c) was designed, synthesized, and reacted ...with imidazole. The optical properties of the corresponding imidazole derivatives 4a–c were analyzed both in solution and in the solid state. Although the solutions display a very weak emission, the powders show a blue emission, particularly enhanced in the case of compound 4c possessing two methoxy groups in the cinnamic scaffold. The photophysical study confirmed the hypothesis that the molecular rigidity of the solid state enhances the emission properties of these compounds by triggering the restriction of intramolecular motions, paving the way for their applications in fluorogenic labeling.
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