Antoni Costa

Cytotoxic anion transporters with light‐regulation properties are highly interesting for the development of anticancer agents with reduced secondary effects. Herein, we present a series of potent diaryl squaramide (SQ) transporters that can be deactivated with light. Liposome‐based assays indicate that the deactivation efficiency depends on the nature of the aryl substituents, with remarkably efficient deactivations observed for cyano‐substituted SQs (i.e., deactivation in only 1 s). Spectroscopic studies suggest that the loss of transport activity is caused by transformation of the SQs into furanone derivatives within the lipid membranes. Finally, cell viability studies show how the cytotoxicity of SQs can be reduced with light, probably by inhibition of an anion transport process in the cell membrane. This study presents the first example of artificial cytotoxic transporters deactivated by direct irradiation in living cells, which can allow selective mitigation of their killing ability.

The stability and hydrolytic behavior of squaramate esters in aqueous solutions have been investigated. The structure of squaramates and the nature of adjacent groups significantly influence their aqueous stability and reactivity towards nucleophiles. Squaramate esters, lacking or containing weakly basic neighboring group participation (NGP) substitutions, remain stable up to pH 9. Their hydrolysis rate (k_OH ≈ 10⁻¹ M⁻¹ s⁻¹) is 1000 times faster than that of squaramides, following a second-order rate law. Squaramate esters functionalized with basic NGP groups, such as amines, display a pH-dependent hydrolysis rate due to anchimeric assistance of the terminal amino group, reducing stability to pH 5. However, when the squaramate ester has a terminal nucleophilic group in the γ position of the alkyl chain, it undergoes rapid intramolecular cyclization, forming cyclic squaramides.

Simple, clean and fast photoconversion of aniline-derived squaramides was achieved by flashlight illumination. UV irradiation enabled the photochemical squaramide ring-opening to generate 1,2-bisketenes, which DMSO trapped as the nucleophilic oxidant. The only photoproducts isolated were 3,4-arylamino maleic anhydrides, which present conformational preferences very different from those of their parent squaramides. Similar photoconversion was achieved in MeOH. The UV-mediated time-dependent anion transport inhibition was demonstrated, establishing a new approach for modulating the transport abilities of AD-squaramides.

CMOS–MEMS microresonators have become excellent candidates for developing portable chemical VOC sensing systems thanks to their extremely large mass sensitivity, extraordinary miniaturization capabilities, and on-chip integration with CMOS circuitry to operate as a self-sustained oscillator. This paper presents two 4-anchored MEMS plate resonators, with a resonance frequency of 2.2 MHz and 380 kHz, fabricated together with the required circuitry using a commercial 0.35 μm CMOS technology and then coated with poly-4-vinylheduorocumyl alcohol (P4V) via inkjet deposition. Such P4V constitutes a functionalization layer for specific acetone detection as a key step in the development of an integrated device for non-invasive diabetes diagnosis through exhaled human breath. The coated sensor system has been proven to increase the acetone injection response by 6-times compared to the uncoated platform and shows a cross-sensitivity to butane of 1 : 11. Experimental data show an acetone sensitivity of −0.012 ppm Hz⁻¹ in the best case that, together with a measured frequency Allan deviation of 0.32 ppm, provides an expected limit of detection as low as 20 ppb of acetone. Additionally, this work presents an alternative resonator design with folded flexure anchors that provide a drastic reduction of the sensor temperature sensitivity and mitigate the impact of a fluid flow inherent to the calibration system.

In the presence of Ag(I), the monoanion of cyano-N-squaraine (I) generates an intense fluorescence turn-on response. Experimental evidence and DFT calculations reveal a sequence of deprotonation-coordination events in which the Ag(I) ions play a dual role as a Lewis acid and coordinating metal. The observed effect is highly selective for Ag(I) compared to other metals.

Herein we report the design, synthesis and assessment of the first example of a squaramide-based self-immolative system triggered by an enzymatic reduction. We have proved that the release of the alkylating agent N′,N′-(bis(2-chloroethyl)benzene)-1,4-diamine (ANM) provokes a dramatic reduction of the survival factor in glioblastoma cells, evidencing the suitability of the squaramide-based spacer for drug delivery applications.

The rising interest on pathway complexity in supramolecular polymerization has prompted the finding of novel monomer designs able to stabilize kinetically trapped species and generate supramolecular polymorphs. In the present work, the exploitation of the Z/E (geometrical) isomerism of squaramide (SQ) units to produce various self‐assembled isoforms and complex supramolecular polymerization pathways in methylcyclohexane/CHCl₃ mixtures is reported for the first time. This is achieved by using a new bissquaramidic macrocycle (MSq) that self‐assembles into two markedly different thermodynamic aggregates, AggA (discrete cyclic structures) and AggB (fibrillar structures), depending on the solvent composition and concentration. Remarkably, UV–vis, ¹H NMR, and FT‐IR experiments together with quantum‐chemical calculations indicate that these two distinct aggregates are formed via two different hydrogen bonding patterns (side‐to‐side in AggA and head‐to‐tail in AggB) due to different conformations in the SQ units (Z,E in AggA and Z,Z in AggB). The ability of MSq to supramolecularly polymerize into two distinct aggregates is utilized to induce the kinetic‐to‐thermodynamic transformation from AggA to AggB, which occurs via an on‐pathway mechanism. It is believed that this system provides new insights for the design of potential supramolecular polymorphic materials by using squaramide units.

Squaramides are versatile compounds with a great capacity to interact via non-covalent interactions and therefore of interest for the development of supramolecular systems and functional materials. In the present work, a new series of aryl-squaramide amphiphiles (1–5) were prepared to form supramolecular polymers in water. Interestingly, only compounds 1 and 2 that contain electron-deficient aryl groups are capable of forming hydrogels (∼10⁻² M) upon treatment with a base (NaOH or PBS). The aggregation behaviour of 1 and 2 was studied by static light scattering, UV-Vis, ¹H NMR, FT-IR, and atomic force microscopy, and it was found that these compounds aggregate forming well-defined 1D nanofibers below the critical gelation concentration (−3 M). Moreover, the combination of these experiments with 1D and 2D NMR studies and theoretical calculations revealed that 1 and 2 self-assemble via an unprecedented interaction motif showing dipolar π–π interactions between the squaramide rings and the 4-nitrophenyl or 3,5-bis(trifluoromethyl)phenyl rings of 1 and 2, respectively. Such kinds of assemblies are stabilized by the compensation of the dipole moments of the stacked molecules. This interaction mode contrasts with those typically driving squaramide-based assemblies based on either hydrogen bonds or antiparallel stacking. We believe that this interaction motif is of interest for the design and development of new squaramide nanomaterials with free hydrogen bonding groups, which might be useful in drug delivery applications.

We report on the bio-inspired growth of gold nanoparticles (GNPs) in biocompatible hydrogels to develop plasmonic hybrid materials. The new hydrogel (CS-Sq) is prepared from chitosan and diethylsquarate and is formed via non-covalent interactions rising between the in-situ formed ionic squaric acid derivatives and chitosan. Interestingly, when the hydrogel is prepared in the presence of HAuCl4, GNPs with controlled sizes between 15 and 50 nm are obtained which are homogeneously distributed within the plasmonic hydrogels (GNPs-CS-Sq). We found that the supramolecular nature and the composition of the CS-Sq hydrogels are key for the GNPs growth process where the squaric derivatives act as reducing agents and the chitosan hydrogel network provides nucleation points and supports the GNPs. Accordingly, the hydrogel acts as a bio-inspired reactor and permits the fine-etuning of the GNPs size by adjusting the concentration of chitosan and HAuCl4. Besides the intrinsic and tunable plasmonic properties of the GNPs-CS-Sq hydrogels, it was found that the gels could be useful as heterogeneous catalysts for organic reactions. Furthermore, cell viability studies indicate that the new hydrogels exhibit suitable biocompatibility. Thus, the proposed method for obtaining GNPs-CS-Sq hydrogels has the potential to be applied for the development of a wide variety of other hybrid chitosan materials useful for catalysis, biosensing, cell culture, tissue engineering, and drug delivery applications.