Gihane Nasr

Dynamic hybrid materials for constitutional self-instructed membranes.

Constitutional self-instructed membranes were developed and used for mimicking the adaptive structural functionality of natural ion-channel systems. These membranes are based on dynamic hybrid materials in which the functional self-organized macrocycles are reversibly connected with the inorganic silica through hydrophobic noncovalent interactions. Supramolecular columnar ion-channel architectures can be generated by reversible confinement within scaffolding hydrophobic silica mesopores. They can be structurally determined by using X-ray diffraction and morphologically tuned by alkali-salts templating. From the conceptual point of view, these membranes express a synergistic adaptive behavior: the simultaneous binding of the fittest cation and its anion would be a case of “homotropic allosteric interactions,” because in time it increases the transport efficiency of the pore-contained superstructures by a selective evolving process toward the fittest ion channel. The hybrid membranes presented here represent dynamic constitutional systems evolving over time to form the fittest ion channels from a library of molecular and supramolecular components, or selecting the fittest ion pairs from a mixture of salts demonstrating flexible adaptation.

Supramolecular self-organization in constitutional hybrid materials

We present in this paper a new strategy to transcribe the supramolecular dynamic self-organization of the G-quadruplex and ureidocrown ether ion channel-type columnar architectures in constitutional hybrids. In particular, the use of a “dynamic reversible hydrophobic interface” can render the emerging hybrid mesophases self-adaptive. The reversible hydrophobic interactions allow both supramolecular and inorganic silica components to mutually (synergistically) adapt their spatial constitution during simultaneous (collective) formation of micrometric self-organized hybrid domains. More generally, applying such consideration to materials, leads to the definition of constitutional hybrid materials, in which organic (supramolecular)/inorganic domains are reversibly connected. This might provide new insights into the features that control the design of functional materials.

Carbonic anhydrase-encoded dynamic constitutional libraries: toward the discovery of isozyme-specific inhibitors.

A constitutional dynamic library (CDL) was generated under thermodynamic control by using the amino-carbonyl/imine interconversion as reversible chemistry, combined with noncovalent bonding within the active site of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Considering the pharmacological importance to find isoform-selective CA inhibitors (CAIs), two of the 15 human (h) isoform, i.e., hCAI and hCA II, have been subjected to a parallel screening of the same CDL. The use of parallel constitutional screening of CDL chemistry for the discovery of enzyme inhibitors is straightforward and it might provide initial insights toward the generation of efficient classes of selective, high affinity inhibitors. We demonstrate here that the high selectivity and specificity of inhibiting the hCA I and hCA II isozymes with some of the detected hits may be used to describe a complex constitutional behavior through component selection from the dynamic library, driven by the selective binding to the specific isoform active site. These results also point to the possibility of modulating the drug discovery methods by constitutional recomposition induced by a specific enzymatic target.

Carbonic anhydrase II-induced selection of inhibitors from a dynamic combinatorial library of Schiff's bases.

A dynamic combinatorial library (DCL) has been generated under thermodynamic control by using the aminocarbonyl/imine interconversion as reversible chemistry, combined with non-covalent binding within the active site of the metalloenzyme human carbonic anhydrase II (hCA II, EC 4.2.1.1). The high affinity of hCA II isozyme towards some sulfonamide inhibitors obtained here was used to select from the dynamic library specific inhibitors of this isoform. These results point out to the possibility of identifying sulfonamide amplified compounds presenting potent inhibition and high yield of formation in the presence of the isoform(s) towards which the inhibitors were designed.

Dithiolate-appended iridium(III) complex with dual functions of reducing and capping agent for the design of small-sized gold nanoparticles.

The unprecedented combined reduction of chloroauric acid and capping of the resulting gold nanoparticles in the absence of an external reducing agent are demonstrated using a novel heteroleptic Ir(III) complex incorporating a 4,5-diazafluorenedithiolate ligand. The reduction process in basic medium results from a cascade mechanism involving oxidation of the ligand, reduction of the gold salt, and stabilization and functionalization of the gold nanoparticles.

Carbonic anhydrase inhibitors. Inhibition of human cytosolic isoforms I and II with (reduced) Schiff's bases incorporating sulfonamide, carboxylate and carboxymethyl moieties.

A library of Schiff bases was synthesized by condensation of aromatic amines incorporating sulfonamide, carboxylic acid or carboxymethyl functionalities as Zn(2+)-binding groups, with aromatic aldehydes incorporating tert-butyl, hydroxy and/or methoxy groups. The corresponding amines were thereafter obtained by reduction of the imines. These compounds were assayed for the inhibition of two cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isoenzymes, hCA I and II. The Ki values of the Schiff bases were in the range of 7.0-21,400nM against hCA II and of 52-8600nM against hCA I, respectively. The corresponding amines showed Ki values in the range of 8.6nM-5.3μM against hCA II, and of 18.7-251nM against hCA I, respectively. Unlike the imines, the reduced Schiff bases are stable to hydrolysis and several low-nanomolar inhibitors were detected, most of them incorporating sulfonamide groups. Some carboxylates also showed interesting CA inhibitory properties. Such hydrosoluble derivatives may show pharmacologic applications.