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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.
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.
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.
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.
A coating technology based on low molecular weight hyaluronic acid (HA) and ferulic acid (FA) was applied to the coating of low generation poly(propylene imine) dendrimers through a biocompatible ...hexa(ethylene glycol) spacer. The ensuing HA‐FA‐HEG‐PPID dendrimeric materials showed interesting loading capability (between 7.65% and 9.08%) regarding anticancer agent doxorubicin, and their interactions with the drug appeared to hamper the drug release in the physiological environment. Thus, the stable nanostructured loaded delivery systems were able to internalize into cells expressing the HA receptor CD44 and to demonstrate high cytotoxicity comparable to that shown by equivalent amounts of free doxorubicin. Thus, HA‐FA‐HEG‐PPID dendrimeric materials were proposed as biocompatible drug carriers capable of transporting anticancer doxorubicin to tumor cells.
The proposed HA‐FA‐HEG‐PPID dendrimeric materials, based on hyaluronic acid (HA) and poly(propylene imine) dendrimers (PPID), show doxorubicin loading and sequestration capability in the physiological environment. The stable nanostructured loaded delivery systems are able to internalize into HCT116 cells and to demonstrate high cytotoxicity comparable to that shown by equivalent amounts of free doxorubicin.
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•Two benzofulvene derivatives bearing a 4-pyridylacetylene substituent in different positions (i. e. 2 and 6) of the benzofulvene scaffold are designed and synthesized.•Both ...benzofulvene derivatives 2-PA-BF3a and 6-PA-BF3k showed the tendency to polymerize spontaneously in the consequence of solvent removal.•NMR and MALDI-TOF studies suggested for poly-6-PA-BF3k a higher structural homogeneity with respect to poly-2-PA-BF3a.•Poly-6-PA-BF3k show an interesting hole mobility value, which was found to be around two orders of magnitude higher than that of poly(vinylcarbazole).
Two benzofulvene derivatives bearing a 4-pyridylacetylene substituent in different positions (i. e. 2 and 6) of the benzofulvene scaffold are designed and synthesized to evaluate the effects on the spontaneous solid-state polymerization of the presence of the same substituent in two different key positions of the 3-phenylbenzofulvene moiety. Both the benzofulvene derivatives showed the tendency to polymerize spontaneously in the consequence of solvent removal under reduced pressure without the addition of catalysts or initiators. The macromolecular structure of the stemming polymeric materials was investigated by NMR spectroscopy and MALDI-TOF mass spectrometry. Both NMR and MALDI-TOF studies confirmed the polymeric nature of the materials and suggested for the polybenzofulvene derivative bearing the 4-pyridylacetylene substituent in positions 6 a higher structural homogeneity with respect to the one bearing the same substituent in position 2. The photophysical characterization of the most homogeneous polybenzofulvene derivative led to the discovery of its outstanding hole mobility value, which was found to be around one order of magnitude higher than that previously measured for two oligothiophene-based polybenzofulvene derivatives and almost two orders of magnitude higher than that of poly(vinylcarbazole), commonly used as hole-transporter matrix. This result places the new polybenzofulvene derivative in an outstanding position as a promising material for field-effect transistor (FET) device applications.
The synthesis of new bis‐deoxy‐coelenterazine (1) derivatives bearing ester protective groups (acetate, propionate and butyrate esters) was accomplished. Moreover, their hydrolytic stability at room ...temperature was evaluated in dimethylsulfoxide (DMSO) as solvent, using the nuclear magnetic resonance (NMR) spectra of the key products at different time intervals. The results showed an increasing hydrolysis rate according to longest aliphatic chain, with a half‐life of 24 days of the more stable acetate derivative (4a). Furthermore, the analysis of the experimental data revealed the greater stability of the enol tautomer in this aprotic polar solvent. This result was confirmed by theoretical calculations using the density functional theory (DFT) approach, which gave us the opportunity to propose a detailed decomposition mechanism. Additionally, the derivatives obtained were tested by bioluminescence luciferase assays to evaluate their potential use as extracellular pH‐sensitive reporter substrates of luciferase. The biological data support the idea that further structural modifications of these molecules may open promising perspectives in this field of research.
Studies on new caged coelenterazine reveal appreciable pH sensitivity, related to their hydrolysis kinetics.
HBDI‐like chromophores represent a novel set of biomimetic switches mimicking the fluorophore of the green fluorescent protein that are currently studied with the hope to expand the molecular ...switch/motor toolbox. However, until now members capable of absorbing visible light in their neutral (i. e. non‐anionic) form have not been reported. In this contribution we report the preparation of an HBDI‐like chromophore based on a 3‐phenylbenzofulvene scaffold capable of absorbing blue light and photoisomerizing on the picosecond timescale. More specifically, we show that double‐bond photoisomerization occurs in both the E‐to‐Z and Z‐to‐E directions and that these can be controlled by irradiating with blue and UV light, respectively. Finally, as a preliminary applicative result, we report the incorporation of the chromophore in an amphiphilic molecule and demonstrate the formation of a visible‐light‐sensitive nanoaggregated state in water.
Exploiting the conjugation of the 3‐phenyl benzofulvene scaffold, we prepared a new HBDI‐like chromophore capable of absorbing blue light and photoisomerizing in the picosecond timescale. The PEGylation of this photoswitch lead to a visible light‐sensitive amphiphilic molecule capable of self‐assembly in water to give a spherical nanoaggregated structure.
The use of light-responsive proteins to control both living or synthetic cells, is at the core of the expanding fields of optogenetics and synthetic biology. It is thus apparent that a richer ...reaction toolbox for the preparation of such systems is of fundamental importance. Here, we provide a proof-of-principle demonstration that Morita-Baylis-Hillman adducts can be employed to perform a facile site-specific, irreversible and diastereoselective click-functionalization of a lysine residue buried into a lipophilic binding pocket and yielding an unnatural chromophore with an extended π-system. In doing so we effectively open the path to the in vitro preparation of a library of synthetic proteins structurally reminiscent of xanthopsin eubacterial photoreceptors. We argue that such a library, made of variable unnatural chromophores inserted in an easy-to-mutate and crystallize retinoic acid transporter, significantly expand the scope of the recently introduced rhodopsin mimics as both optogenetic and "lab-on-a-molecule" tools.
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