Juan V. Alegre-Requena

Metal–organic frameworks (MOFs) bring new life to hydrogen-bonding organocatalysts in confined spaces

Hydrogen-bonding organocatalysis has emerged as a promising biomimetic alternative to Lewis acid catalysis. Urea, thiourea and squaramide moieties represent the most common hydrogen-bond donors used for the preparation of these catalysts. However, their significant tendency to undergo self-quenching (self-aggregation) often decreases their solubility and reactivity. Recently, scientists have found a promising way around this problem by immobilizing the hydrogen-bonding organocatalysts on metal–organic frameworks (MOFs). Along with advantageous modular synthesis and recycling properties, the tunable porosity and topology of MOFs also allows fast mass transport and/or interactions with substrates. Herein, we highlight the existing examples dealing with the fabrication and testing of hydrogen-bonding organocatalyst-containing MOFs, providing also our vision for further advances in this area. The results derived from these studies will likely serve as inspiration for the future development of superior hydrogen-bonding organocatalysts to accomplish in confined spaces chemical transformations that are either slow or unaffordable under standard homogeneous conditions.

One-pot synthesis of unsymmetrical squaramides

The results concerning the first one-pot synthesis of unsymmetrical squaramides are reported. This straightforward procedure allows appealing and commonly used squaramide derivatives to be obtained with very good results. The methodology developed in this work saves energy, eliminates the purification steps for intermediate products, reduces costs and leads to better yields compared to those obtained through the traditional “stop-and-go” approach. Moreover, we have proved the efficiency of our process with the synthesis of three biologically active structures, improving the results of the previously reported stepwise syntheses. Interestingly, this simple and cheap method could attract the interest of pharmaceutical and chemical companies aiming to produce these active compounds on a large scale.

Regulatory parameters of self-healing alginate hydrogel networks prepared via mussel-inspired dynamic chemistry

Several key parameters that influence both the self-healing properties and water retention capacity of biohydrogel networks made of alginate–dopamine (Alg–DA) conjugates have been studied. A judicious combination of biopolymer concentration, dopamine content, pH-dependent cross-linking of catechol groups and the Fe3+-coordination of the networks allowed control over the self-healing ability of these bioinspired materials. Moreover, the thixotropic nature of model hydrogels was confirmed using oscillatory rheological loop tests.

Synthesis of luminescent squaramide monoesters: cytotoxicity and cell imaging studies in HeLa cells

Novel luminescent squaramide monoesters functionalised with different fluorophore groups have been synthesised and explored in cell imaging for the first time. Cytotoxicity studies performed in HeLa cervical cancer cells revealed high activity for some of these novel structures, highlighting the importance of the fluorescent fragment in the efficiency of these promising anticancer agents. In addition, fluorescence cell microscopy disclosed the different biodistribution behaviour depending on the fluorescent moiety, and the possibility of nuclear localisation of chiral non planar squaramide monoesters.

Guanidine Motif in Biologically Active Peptides

In the past decade, guanidines have attracted attention as valuable hydrogen bond-based catalysts while they have long been considered as organic superbases with a broad scope of synthetic applicability. Their easy modification has also expanded their capacity to form complexes with a wide range of metal salts as effective metal scavengers. All these attractive aspects have promoted a huge growth in the field of organic synthesis involving guanidines and examples of such reactions have been collected in numerous reviews and some books. Moreover, this structural motif is also present in a large number of natural products and biologically active compounds that exhibit appealing properties and play important roles in medicinal chemistry. In this highlight, we will only cover the synthesis and properties of biologically active guanidine-containing peptides reported in the past 3 years.

Optimizing the Accuracy and Computational Cost in Theoretical Squaramide Catalysis: The Henry Reaction

This study represents the first example where the accuracy of different combinations of density functional theory (DFT) methods and basis sets have been compared in squaramide catalysis. After an optimization process of the precision obtained and the computational time required in the computational calculations, highly precise results were achieved compared to the experimental outcomes while requiring the least amount of time possible. Here, we have explored computationally and experimentally the mechanism of the squaramide-catalyzed Henry reaction. This is a complex reaction of about 100 atoms and a great number of diverse non-covalent interactions. Moreover, this research is one of the scarce examples where the organocatalyst acts in a trifunctional manner and is the first investigation in which a trifunctional squaramide catalyst has been employed. Functional ωB97X-D showed the best results when used with different versions of the 6-311 basis sets, leading to highly accurate calculations of the outcomes of the Henry reaction when using nine aldehydes with different structural characteristics. Furthermore, in these relatively large systems, the use of a split-valence triple-zeta basis set saves a large amount of time compared with using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families.

Squaramides with cytotoxic activity against human gastric carcinoma cells HGC-27: synthesis and mechanism of action

A series of squaramates and squaramides have been synthesized and their cytotoxic activity has been investigated in different cancer cell lines. Among the studied compounds, squaramide 34 showed a potent and selective cytotoxicity against the human gastric cancer cell line HGC-27. Studies directed to elucidate the mechanism of induced cell death were performed. Cell cycle distribution analysis and cell death studies showed that compound 34 induces cell cycle arrest at the G1 phase and caspase-dependent apoptosis. In conclusion, squaramide 34 can be considered a potential anticancer agent for gastric carcinoma.

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides

We describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long aliphatic chain and on the other side to a glutamic acid residue. The gelator bearing the free carboxylic groups showed a lower gelation capacity than its precursor diester derivative. Some selected gels were further studied by infrared spectroscopy, rheology and electron microscopy. Critical gelation concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition.

Synthesis of Luminescent Squaramide Monoesters: Cytotoxicity and Cell Imaging Studies in HeLa Cells

Novel luminescent squaramide monoesters functionalised with different fluorophore groups have been synthesized and explored in cell imaging for the first time. Cytotoxicity studies performed in HeLa cervical cancer cells revealed high activity for some of these novel structures, highlighting the importance of the fluorescent fragment in the efficiency of these promising anticancer agents. In addition, fluorescence cell microscopy disclosed the different biodistribution behaviour depending on the fluorescent moiety, and the possibility of nuclear localisation of chiral non planar squaramide monoesters.