Carmen Rotger

Substituent effects on cation–π interactions: A quantitative study

A synthetic supramolecular complex has been adapted to quantify cation–π interactions in chloroform by using chemical double-mutant cycles. The interaction of a pyridinium cation with the π-face of an aromatic ring is found to be very sensitive to the π-electron density. Electron-donating substituents lead to a strong attractive interaction (−8 kJ/mol−1), but electron-withdrawing groups lead to a repulsive interaction (+2 kJ/mol−1).

Squaramide-based reagent for selective chromogenic sensing of Cu(II) through a zwitterion radical.

A minimalist squaramide-based chemodosimeter for Cu(2+) is described. Upon selective chelation to 2, Cu(2+) induces the formation of a highly colored zwitterionic radical, which is kinetically stable for hours. The presence of a radical is confirmed by EPR and ESI-MS. It is then possible to use reagent 2 for visual and selective sensing of Cu(2+) at neutral pH.

Janus-like squaramide-based hosts: dual mode of binding and conformational transitions driven by ion-pair recognition.

New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D(6)]DMSO in CDCl(3), compound 4 formed dimeric assemblies [log K(dim)=3.68(8)] as demonstrated by (1)H NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C(3)-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N-H⋅⋅⋅X(-) hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=O⋅⋅⋅H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high-order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR(4)I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition.

Selective sensing of competitive anions by non-selective hosts: the case of sulfate and phosphate in water

Two sensing ensembles based on the common squaramide host 2 and the acid–base indicators Cresol Red (CR) and Bromocresol Green (BG) are described. Both couples were characterized in EtOH–H2O mixtures by UV-Vis spectroscopy. Analysis of the binding curves and the corresponding Job plots indicate 1 : 1 binding between the indicators CR or BG and host 2. The sensing solutions are responsive to sulfate and/or phosphate anions in water, changing the coloration of the solution. As in other indicator displacement assays (IDA), host 2 translates the chemical event into a colorimetric response that is analyzed by spectrophotometry. However, since other anions present in natural waters do not result in color changes, this method allows the quantification of sulfate and phosphate in water.

Evidence of anion-induced dimerization of a squaramide-based host in protic solvents

The combination of squaramide units with tetraalkylammonium groups leads two hosts that bind distinctively dianions in water-ethanol mixtures. The formation of complexes of 2:1 stoichiometry with host was supported by ITC, fluorescence, and (1)H NMR data.

Grafted squaramide monoamine nanoparticles as simple systems for sulfate recognition in pure water

New simple systems formed by a chain containing a squaramide function and a quaternised amine group attached to boehmite or silica-coated boehmite nanoparticles are able to discriminate anions in pure water.

Programmed enzyme-mimic hydrolysis of a choline carbonate by a metal-free 2-aminobenzimidazole-based cavitand.

The hydrolysis of a choline carbonate through a metal-free, enzyme-like mechanism has been achieved using a 2-aminobenzimidazole-based deep cavitand as catalyst. The supramolecular catalysis involves three steps: host-guest binding, carbamoylation and enzyme-like hydrolysis. Interestingly the rate-determining step proceeds through a programmed hydrolysis of carbamoylcholine-cavitand intermediate that may be driven by water molecules surrounding the benzimidazole walls of the cavity.

Cyclosquaramides as Kinase Inhibitors with Anticancer Activity

We report the synthesis and biological evaluation of a new series of oligosquaramide‐based macrocycles as anticancer agents. Compound 7, considered as representative of this series, exhibited significant antiproliferative activity against the NCI‐60 human tumor cell line panel, with IC50 values ranging from 1 to 10 μM. The results show that sensitivity to cyclosquaramides is clearly dependent on cell type, underscoring a degree of biological selectivity. The observed antiproliferative effects appear to be related to deregulation of protein phosphorylation, as compounds 7 and 8 are effective inhibitors of several important kinases such as ABL1, CDK4, CHK1, PKC, c‐MET, and FGFR, among others. The corresponding acyclic oligosquaramides and smaller cyclosquaramides did not show antitumor activity, suggesting that a macrocyclic structure with minimal molecular size plays a key role in the observed antitumor activity.

Cell Uptake and Localization Studies of Squaramide Based Fluorescent Probes

Cell internalization is a major issue in drug design. Although squaramide-based compounds are receiving much attention because of their interesting bioactivity, cell uptake and trafficking within cells of this type of compounds are still unknown. In order to monitor the cell internalization process of cyclosquaramide compounds we have prepared two fluorescent probes by covalently linking a fluorescent dye (BODIPY derivative or fluorescein) to a noncytotoxic cyclosquaramide framework. These two probes (C2-BDP and C2-FITC) rapidly internalize across live cell membranes through endocytic receptor-mediated mechanisms. Due to its higher fluorescence and photochemical stability, C2-BDP is a superior dye than C2-FITC. C2-BDP remains sequestered in late endosomes allowing their fast and selective imaging in various live cell types. Cyclosquaramide-cell membrane interactions facilitate cell uptake and have been investigated by binding studies in solution as well as in live cells. Cyclosquaramide 1 (C2-BDP) can be used as a highly fluorescent probe for the rapid and selective imaging of late endosomes in live cells.

HYDROGEN-BOND RECOGNITION OF CYCLIC DIPEPTIDES IN WATER

An amide macrocycle with a highly preorganised cavity containing both polar and non-polar recognition sites forms stable complexes with cyclic dipeptides in water via amide–amide hydrogen-bonds, NH–π hydrogen-bonds and hydrophobic contacts.