Design and synthesis of unnatural coordination glycopolymer particles (CGPs): unleashing the potential of catechol-saccharide derivatives.

Our study unveils an innovative methodology that merges catechols with mono- and disaccharides, yielding a diverse array of compounds. This strategic fusion achieves robust yields and introduces ligands with a dual nature: encompassing both the chelating attributes of catechols and the recognition capabilities of carbohydrates. This synergistic design led us to couple one of the novel ligands with an Fe(iii) salt, resulting in the creation of Coordination Glycopolymer Particles (CGPs). These CGPs demonstrate remarkable qualities, boasting outstanding dispersion in both aqueous media and Phosphate Buffered Saline (PBS) solution (pH ∼7.4) at higher concentrations (0.26 mg µL-1). Displaying an average Z-size of approximately 55 nm and favourable polydispersity indices (<0.25), these particles exhibit exceptional stability, maintaining their integrity over prolonged periods and temperature variations. Notably, they retain their superior dispersion and stability even when subjected to freezing or heating to 40 °C, making them exceptionally viable for driving biological assays. In contrast to established methods for synthesizing grafted glycopolymers, where typically a glycopolymer is doped with catechol derivatives to create synergy between chelating properties and those inherent to the saccharide, our approach provides a more efficient and versatile pathway for generating CGPs. This involves combining catechols and carbohydrates within a single molecule, enabling the fine-tuning of organic structure from a monomer design step and subsequently transferring these properties to the polymer.

Hydrothiolation of alkynes with thiol-catechol derivatives catalysed by CuNPs/TiO2: exploring the reaction mechanism by DFT calculations.

Density functional theory (DFT) calculations were applied to describe the hydrothiolation reaction of activated alkynes with thiols bearing a catechol group. The thiol-yne click (TYC) process was efficiently catalysed by a CuNPs/TiO2 nanocatalyst giving the corresponding anti-Markovnikov vinyl sulphides with high Z-stereoselectivity. Based on the experimental results and DFT studies, a plausible reaction mechanism is proposed, which implies the activation of the carbon-carbon triple bond by coordination to the copper centre, followed by a stereoselective (external) nucleophilic attack to give preferentially the Z-vinyl sulphide isomer. Additionally, experimental and theoretical studies strongly correlate with the proposed synergistic role for the TiO2 support in the catalytic process.

Novel pH-sensitive catechol dyes synthesised by a three component one-pot reaction.

The synthesis and characterisation of new dyes based on indolizines bearing catechol groups in their structure is presented. The preparation was carried out through a simple three component one-pot reaction promoted by CuNPs/C, between pyridine-2-carbaldehyde, an aromatic alkyne and a tetrahydroisoquinoline (THIQ) functionalized with catechol groups. The products were isolated in 30%-34% yield, which was considered more than acceptable considering that the catechol hydroxyl groups were not protected prior to reaction. In view of the colour developed by the products and their response to the acidic and basic conditions of the medium, product 3aa was studied by UV-Vis and NMR spectroscopies at different pH values. We concluded that product 3aa suffered two deprotonations at pKa of 4.4 and 9.5, giving three species in a pH range between 2-12, with colours varying from light red to deep orange. The reversibility of the process observed for 3aa at different pH values, together with its changes in colour, make this new family of products attractive candidates to use them as pH indicators.

Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson's Disease.

Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson's disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood-brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 µg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy.

Thiol-yne click reaction: an interesting way to derive thiol-provided catechols.

The hydrothiolation of activated alkynes is presented as an attractive and powerful way to functionalize thiols bearing catechols. The reaction was promoted by a heterogeneous catalyst composed of copper nanoparticles supported on TiO2 (CuNPs/TiO2) in 1,2-dichloroethane (1,2-DCE) under heating at 80 °C. The catalyst could be recovered and reused in three consecutive cycles, showing a slight decrease in its catalytic activity. Thiol derivatives bearing catechol moieties, obtained through a versatile Michael addition, were reacted with different activated alkynes, such as methyl propiolate, propiolic acid, propiolamide or 2-ethynylpyridine. The reaction was shown to be regio- and stereoselective towards anti-Markovnikov Z-vinyl sulfide in most cases studied. Finally, some catechol derivatives obtained were tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the advantage of their different coordination sites with metals such as iron and cobalt.

Bioinspired Functional Catechol Derivatives through Simple Thiol Conjugate Addition.

The combination of the surface-adhesive properties of catechol rings and functional moieties conveying specific properties is very appealing to materials chemistry, but the preparation of catechol derivatives often requires elaborate synthetic routes to circumvent the intrinsic reactivity of the catechol ring. In this work, functional catechols are synthesized straightforwardly by using the bioinspired reaction of several functional thiols with o-benzoquinone. With one exception, the conjugated addition of the thiol takes place regioselectively at the 3-position of the quinone, and is rationalized by DFT calculations. Overall, this synthetic methodology provides a general and straightforward access to functional and chain-extended catechol derivatives, which are later tested with regard to their hydro-/oleophobicity, colloidal stability, fluorescence, and metal-coordinating capabilities in proof-of-concept applications.

Polydopamine-like Coatings as Payload Gatekeepers for Mesoporous Silica Nanoparticles.

We report the use of bis-catecholic polymers as candidates for obtaining effective, tunable gatekeeping coatings for mesoporous silica nanoparticles (MSNs) intended for drug release applications. In monomers, catechol rings act as adhesive moieties and reactive sites for polymerization, together with middle linkers which may be chosen to tune the physicochemical properties of the resulting coating. Stable and low-toxicity coatings (pNDGA and pBHZ) were prepared from two bis-catechols of different polarity (NDGA and BHZ) on MSN carriers previously loaded with rhodamine B (RhB) as a model payload, by means of a previously reported synthetic methodology and without any previous surface modification. Coating robustness and payload content were shown to depend significantly on the workup protocol. The release profiles in a model physiological PBS buffer of coated systems (RhB@MSN@pNDGA and RhB@MSN@pBHZ) showed marked differences in the "gatekeeping" behavior of each coating, which correlated qualitatively with the chemical nature of their respective linker moieties. While the uncoated system (RhB@MSN) lost its payload almost completely after 2 days, release from RhB@MSN@pNDGA was virtually negligible, likely due to the low polarity of the parent bis-catechol (NDGA). As opposed to these extremes, RhB@MSN@pBHZ presented the most promising behavior, showing an intermediate release of 50% of the payload in the same period of time.

Synthesis of Polydopamine-Like Nanocapsules via Removal of a Sacrificial Mesoporous Silica Template with Water.

Hollow polymeric polydopamine (PDA) micro-/nanocapsules have been obtained through a very simple, mild, and straightforward method that involves coating of silica mesoporous nanoparticles through an ammonia-triggered polymerization of PDA and the posterior removal of the sacrificial template simply by dispersion in water, without the need of any harsh chemical reagent, either in the presence or absence of active principles, from doxorubicin to iron oxide nanoparticles. To demonstrate the potential of the nanocapsules obtained with this new approach, they have been successfully used as nanocarriers for drug delivery.

Carboxyl group (-CO2 H) functionalized coordination polymer nanoparticles as efficient platforms for drug delivery.

Functionalization of nanoparticles can significantly influence their properties and potential applications. Although researchers can now functionalize metal, metal oxide, and organic polymer nanoparticles with a high degree of precision, controlled surface functionalization of nanoscale coordination polymer particles (CPPs) has remained a significant challenge. The lack of methodology is perhaps one of the greatest roadblocks to the advancement of CPPs into high added-value drug delivery applications. Here, we report having achieved this goal through a stepwise formation and functionalization protocol. We fabricated robust nanoparticles with enhanced thermal and colloidal stabilities by incorporation of carboxyl groups and these surface carboxyl groups could be subsequently functionalized through well-known peptide coupling reactions. The set of chemistries that we employed as proof-of-concept enabled a plethora of new functional improvements for the application of CPPs as drug delivery carriers, including enhanced colloidal stabilities and the incorporation of additional functional groups such as polyethylene glycol (PEG) or fluorescent dyes that enabled tracking of their cellular uptake. Finally, we ascertained the cytotoxicity of the new CPP nanoparticles loaded with camptothecin to human breast adenocarcinoma (MCF-7). Efflux measurements show that the encapsulation of camptothecin enhances the potency of the drug 6.5-fold and increases the drug retention within the cell.

One-step synthesis of xanthones catalyzed by a highly efficient copper-based magnetically recoverable nanocatalyst.

A versatile and highly efficient strategy to construct a xanthone skeleton via a ligand-free intermolecular catalytic coupling of 2-substituted benzaldehydes and a wide range of phenols has been developed. For this purpose, a novel and magnetically recoverable catalyst consisting of copper nanoparticles on nanosized silica coated maghemite is presented. The reaction proceeds smoothly with easy recovery and reuse of the catalyst. The methodology is compatible with various functional groups and provides an attractive protocol for the generation of a small library of xanthones in very good yield.