The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as ...Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1
-inden-1-one (
), which in the
isomeric form (and about tenfold less in the UV-B photo-induced isomer
) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs
-
with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable
geometric isomer, along with the
mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75%
), was investigated for the inhibition of human ChEs and MAOs. The pure
-isomer of the N-benzyl(ethyl)amino analog
achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC
s 39 and 355 nM, respectively), whereas photoisomerization to the
isomer (75%
in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different
/
selectivity of
toward the two target enzymes.
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.
•Cellulose dichlorophenylcarbamate CSPs enable the enantioseparation of sulfoxides.•Polar-ionic conditions are suitable to obtain high levels of enantioselectivity.•Experimental ECD analyses and ...TD-DFT simulations allow to establish the EEO.•Docking studies allow to identify the selector-selectand interactions.
Chiral sulfoxides represent a class of substances of great importance in many fields, including medicinal chemistry dealing with the synthesis of novel cyclooxygenase-2 (COX-2) inhibiting/NO donors. In the present study, two nitrooxyethyl sulfoxides along with their metabolites, hydroxyethyl derivatives have been successfully enantioresolved with two cellulose tris(3,5-dichlorophenylcarbamate)-based chiral stationary phases (CSPs), one with a coated (CSP 1) and the other (CSP 2) with an immobilized chiral selector. The immobilized selector in CSP 2 produced comparable-to-better performances than the coated one in CSP 1 (with α and RS values up to 1.94 and 6.32, respectively) running the analysis with a polar-organic phase made up with an ethanol/2-propanol (80:20, v/v) mobile phase. Electronic circular dichroism studies coupled to ab initio time-dependent density functional theory simulations allowed us to determine the elution order of three out of four compounds. For the two hydroxyethyl derivatives the same enantiomeric elution order (S)<(R) was obtained with both CSPs, while the compounds containing the −ONO2 group experienced a different elution order depending on the coated or immobilized nature of the chiral selector (S)<(R) with CSP 1 and (R)<(S) with CSP 2. A molecular modeling study based on docking simulations was performed to gain a deeper insight into the enantioseparation mechanism of the hydroxyethyl derivatives on both CSPs.
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A new Morita-Baylis-Hillman Adduct (MBHA) derivative 7 was designed and synthesized to obtain a reactive molecule potentially capable of labelling basic amino acid residues. Compound 7 was easily ...prepared and characterized from the point of view of its photophysical and photochemical features before then to be used in labelling experiments with amino acid.
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•A new Morita-Baylis-Hillman derivative was designed to obtain a reactive molecule capable of labelling basic amino acids.•This compound was promptly synthesized in three steps from commercially available intermediates.•This compound showed an intriguing photochemical activity, which was characterized by photophysical and NMR studies.•These results pave the way for the use of the derivative in the fluorogenic labeling of proteins.
A Morita-Baylis-Hillman acetate was dimerized by a click-chemistry Copper(
i
)-Catalysed Azide-Alkyne Cycloaddition (CuAAC) reaction employing a tri(ethylene glycol) diazide derivative to obtain a ...dimeric MBHA derivative. The reaction of this dimeric MBHA derivative with
n
-butylamine afforded a photoisomerizable macrocyclic crown ether-paracyclophane hybrid architecture that is potentially useful in a large variety of applications as well as those already well-known for crown ethers.
A tri(ethylene glycol)-tethered MBHA dimer was synthesized and found to react with
n
-butylamine leading to the formation of macrocyclic crown ether-paracyclophane hybrid structures that could be modulated by light.
Translocator protein 18 kDa TSPO or peripheral-type benzodiazepine receptor (PBR) was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these ...areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.
A Morita-Baylis-Hillman Adduct (MBHA) derivative bearing a triphenylamine moiety was found to react with human serum albumin (HSA) shifting its emission from the blue to the green-yellow thus leading ...to green fluorescent albumin (GFA) derivatives and enlarging the platform of probes for aggregation-induced fluorescent-based detection techniques. A possible interaction of MBHA derivative 7 with a lipophilic pocket within the HSA structure was suggested by docking studies. DLS experiments showed that the reaction with HSA induce a conformational change of the protein contributing to the aggregation process of GFA derivatives. The results of investigations on the biological properties suggested that GFA retained the ability of binding drug molecules such as warfarin and diazepam. Finally, cytotoxicity evaluation studies suggested that, although the MBHA derivative 7 at 0.1 μg/mL affected the percentage of cell viability in comparison to the negative control, it cannot be considered cytotoxic, whereas at all the other concentrations≥0.5 μg/mL resulted cytotoxic at different extent.
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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