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The kinetics of ligand exchange at a ZnII center confined in a biomimetic environment is studied. The metal ion is bound to a TMPA unit covalently capping the calix[6]arene core. As such, the system is rigidified in a cone conformation open to the solvent at the large rim. At the small rim, the methyl groups of the anisole units lead to steric crowding, thus defining a small pore leading to the metal center. The exchange of an organic guest ligand (MeCN) for another (EtCN) is studied by 1H NMR spectroscopy. It is shown that it is very slow under dry conditions (several hours at mM concentrations), but much faster in the presence of appreciable amounts of water. Kinetic analyses indicate that the exchange process involves the transient formation of an aqua complex that was independently synthesized and well characterized. Computer studies suggest that transient water coordination first occurs through the small rim pore, in exo-position. The water molecule then flips in endo-position, as the MeCN guest decoordinates and exits from the cavity through the large rim. This allows another organic guest ligand to get in, with release of the catalytic water to the solvent. Steered molecular dynamics simulations also show the assistance of the second coordination sphere of the metal ion for the exo/endo flipping process of the water ligand through H-bonding to the oxygenated small rim of the calixarene macrocycle. Importantly, it appeared that only water can play such a catalytic role, due to size selection by the pores defined by the calixarene small rim. From a biological point of view, it further substantiates the importance of water molecules and micro-environment on metal ion lability., SCOPUS: ar.j, info:eu-repo/semantics/published

Lactate dehydrogenases (LDHs) are tetrameric enzymes of therapeutic relevance for cancer therapy due to their important implications in cancer cell metabolism. LDH active site inhibition suffers from different drawbacks due to several features such as high cellular concentration and a shared active site among the dehydrogenase family. Conversely, targeting the LDH oligomeric state is an exciting strategy that could provide a suitable alternative to active-site inhibition. In the present study, we developed a biophysical screening cascade to probe the LDHs tetrameric interface. Using nanoscale differential fluorimetry (nanoDSF) as a primary screening method, we identified a series of hits that destabilize the tetrameric protein. From this primary screening, we validated selected hits using saturation transfer difference nuclear magnetic resonance (STD NMR) and microscale thermophoresis (MST) as a combination of orthogonal biophysical techniques. Finally, we characterized the validated hits and demonstrated that they specifically interact at the tetrameric interface of LDH-1 and LDH-5 and can inhibit the LDH tetramerization process. Overall, this work provides a convenient method for screening ligands at the LDH tetrameric interface and has identified promising hits suitable for further optimization. We believe that this biophysical screening cascade, especially the use of (nano)DSF, could be extended to other homomeric proteins.

N-Salicylideneaniline (also called anil) is a compound which exhibits photochromism (reversible color change induced by light) in the solid-state. Such a feature is quite rare and requires in-deep studies to fully understand it, especially because it can be quite useful in many industrial applications such as secured inks (for banknotes for instance), screens or even optical data storage. Within this thesis, N-Salicylideneaniline and many of its derivatives (the “anils”) were studied in the scope of crystal engineering in order to establish a structure-property relationship and to improve its properties. More specifically, cocrystals were researched and studied using small organic molecules (such as carboxylic acids, amides, amines, benzene halides) as coformers. This resulted in the identification of about 100 cocrystals through the use of X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SC-XRD), diffuse reflectance spectroscopy (DRS), thermal analysis such as thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) along with a few other methods such as Raman spectroscopy. The amount of collected data allowed to show a correlation between the number of intermolecular interactions involving the “moving moiety” of the anils and the presence of photochromism. We also present here a new approach of the Diffuse Reflectance Spectroscopy data treatment, which allows a better classification of the photochromic properties and also allowed the discovery of “weakly” photochromic compounds. These results encourage a revision of the old-empirical “dihedral angle rule” especially because a link between the intensity of photochromism and the torsion angle has been observed in this work. In the last part, we focused on cocrystals containing 2 different anils (instead of one anil and one coformer) and this allowed to observe the existence of a complex multi-phases binary diagram in the case of N-Salicylideneaniline/ N-Salicylidene-4-fluoroanil, (SC - Sciences) -- UCL, 2022

Arginase 1 (Arg1) is a key hydrolase involved in the urea cycle and in the immune system. Arg1 is upregulated in various types of cancers and plays crucial roles in the regulation of tumor growth and metastasis. Thus, Arg1 is an increasingly attractive target for cancer therapy. In this thesis, we aimed to find new scaffolds. A reliable enzymatic evaluation method of chemical libraries such as that of 5-bromo-2-amino-thiazole was set up. A molecular modeling approach (SBDD) led to a better understanding of the possibilities and limitations in the Arg1 inhibitors design for the study of larger scaffolds. A Fragment-Based approach (FBDD) was then developed. A screening of coordinating motif libraries found two hits: 2-furanylboronic acid and cyclohexylboronic acid. Finally, we attempt to optimize these two hits and discussed about the challenges of obtaining such derivatives., (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2022

Metal-organic frameworks (MOFs) are porous coordination tri-dimensional assemblies with potential use for many applications, and especially in catalysis, gas storage and adsorption from solution. The work presented in this thesis mainly aims at improving the sustainable production of MOFs containing trimesate linkers, with well-characterized structures, as well as at the introduction of new types of active sites, under the form of second (“exotic”) metals, amine functions and defects, by easy to implement synthetic approaches. The main part of this thesis concerns the development of a new green aqueous strategy for obtaining the mesoporous MOF MIL 100(Fe) through the use of alkali trimesate salts and the investigation of the MOF’s formation mechanism. This synthetic strategy was further developed to allow incorporation of a second metal to obtain bimetallic MIL 100(Fe,M) incorporating transition, p-bloc and rare-earth elements as secondary metals in a one-pot fashion. The functionalization of mono- and bimetallic Al- and Fe-based MIL 100 MOFs with ethylenediamine (EN) was also investigated, including the CO2 adsorption performances and possibility to post-functionalize the obtained materials. Synthetic efforts were also made to improve the sustainability of the synthesis of lanthanide-based MOF 76 metal-organic frameworks, and increasing their stability towards water by linker modification. Finally, the synthesis of a new type of TiIII-based MOF, NH2 MIL 101(TiIII), was achieved, and the introduction of structural defects induced by mechanosynthesis was studied on HKUST 1 as model MOF. The new materials obtained in this work may find use in multiple applications, such as catalysis and gas sorption., (SC - Sciences) -- UCL, 2022