Luciano Barluzzi

The P2X purinergic receptor 7 (P2X7) has an essential role in inflammation, innate immunity, tumor progression, neurodegenerative diseases, and several other diseases, leading subsequently to the development of P2X7 modulators. AZ11645373 is a frequently studied P2X7 antagonist tool compound but always used as a racemic mixture. Racemic AZ11645373 can be separated into its respective enantiomers by chiral chromatography, albeit in small batches, and these were stereochemically intact over two years later, by chiral high-performance liquid chromatography (HPLC) analysis. On a higher scale, significant decomposition is observed during purification. One of the enantiomers was crystallized as a palladium complex, and its (R)-configuration was determined by single-crystal X-ray diffraction, further confirmed, in solution, by vibrational circular dichroism. Biological studies demonstrated that both (S)- and (R)-forms were able to fully inhibit human P2X7, but (R)-AZ11645373 was more potent, with an IC₅₀ of 32.9 nM. Contrary to its effect on human P2X7, (S)-AZ11645373 was ineffective on mouse P2X7, while the (R)-AZ11645373 enantiomer was a full antagonist. These results demonstrated that the antagonistic effects of racemic AZ11645373 are mainly due to its (R)-enantiomer. Site-directed mutagenesis and molecular dynamics simulations indicated that the (R)-enantiomer may form specific interactions with Phe95 and the antagonists bound to other P2X7 monomers. Phe95 is situated in the allosteric binding site at the edge of the upper vestibule and appears to be the pivotal molecular gateway between AZ11645373 allosteric binding and locking of the closed state of the P2X7 channel. All together, these structure-function relationships should be helpful for drug design of P2X7 modulators.

The P2X purinergic receptor 7 (P2X7) has an essential role in inflammation, innate immunity, tumor progression, neurodegenerative diseases, and several other diseases, leading subsequently to the development of P2X7 modulators. AZ11645373 is a frequently studied P2X7 antagonist tool com-pound, but always as a racemic mixture. Racemic AZ11645373 can be separated, into its respective enantiomers by chiral chromatography, albeit in small batches, and these were stereochemically in-tact over a year later, by chiral HPLC analysis. On a higher scale, significant decomposition is ob-served. One of the enantiomers was crystallised as a palladium complex and its (R)-configuration was determined by single crystal X-ray diffraction, further confirmed, in solution, by vibrational circular dichroism. Biological studies demonstrated that both (S)- and (R)-forms were able to fully inhibit human P2X7, but (R)-AZ11645373 was more potent, with an IC50 of 32.9 nM. Contrary to its effect on human P2X7, (S)-AZ11645373 was ineffective on mouse P2X7, while the (R)-AZ11645373 enantiomer was a full antagonist. These results demonstrated that the antagonistic effects of racemic AZ11645373 are mainly due to its (R)-enantiomer. Site-directed mutagenesis and molecular dynam-ics simulations indicated that the (R)-enantiomer may form specific interactions with Phe95 and the antagonists bound to the other P2X7 monomers. Phe95 is situated at the channel pore and appears to be the pivotal molecular gateway between AZ11645373 allosteric binding and locking of the closed state of the P2X7 channel. All together, these structure-function relationships should be helpful for drug design of P2X7 modulators.

Reduction of the neutral U ^IV –X–U ^IV (X = O or S) complexes supported by aryloxide ligands yielded the U ^IV /U ^III and U ^III /U ^III analogues. Notably, U ^III –S–U ^III is the first example of a U( iii ) sulphide-bridged complex.

Aromatic π-stacking is a weakly attractive, noncovalent interaction often found in biological macromolecules and synthetic supramolecular chemistry. The weak nondirectional nature of π-stacking can present challenges in the design of materials owing to their weak, nondirectional nature. However, when aromatic π-systems contain an unpaired electron, stronger attraction involving face-to-face π-orbital overlap is possible, resulting in covalent so-called "pancake" bonds. Two-electron, multicenter single pancake bonds are well known, whereas four-electron double pancake bonds are rare. Higher-order pancake bonds have been predicted, but experimental systems are unknown. Here, we show that six-electron triple pancake bonds can be synthesized by a 3-fold reduction of hexaazatrinaphthylene (HAN) and subsequent stacking of the [HAN]^3- triradicals. Our analysis reveals a multicenter covalent triple pancake bond consisting of a σ-orbital and two equivalent π-orbitals. An electrostatic stabilizing role is established for the tetravalent thorium and uranium ions in these systems. We also show that the electronic absorption spectrum of the triple pancake bonds closely matches computational predictions, providing experimental verification of these unique interactions. The discovery of conductivity in thin films of triply bonded π-dimers presents new opportunities for the discovery of single-component molecular conductors and other spin-based molecular materials.

The synthesis of acylpyrazolone salts and their complexes of main group elements, transition metals, lanthanides, and actinides are described and characterized inter alia by means of single-crystal X-ray crystallography, NMR, and IR spectroscopies. The complexes consist of two, three, or four acylprazolone ligands bound to the metal atom, resulting in a structurally diverse set of coordination complexes with (distorted) octahedral, pentagonal-bipyramidal, or antiprismatic arrangements. Several complexes proved to be polymeric in the solid state including heterobimetallic sodium/lanthanide coordination polymers. A selection of the polymeric compounds was analyzed via TG/DTA measurements to establish their stability. The ligands, in turn, were readily synthesized in good yields from commercially available hydrazine hydrochloride salts. These findings demonstrate that acylpyrazolone ligands can form complexes with metals of varying ionic radii, highlighted by their utility in other areas such as analytical and metal organic framework chemistry.

The concept of oxidation state plays a fundamentally important role in defining the chemistry of the elements. In the f block of the periodic table, well-known oxidation states in compounds of the lanthanides include 0, +2, +3 and +4, and oxidation states for the actinides range from +7 to +2. Oxidation state +1 is conspicuous by its absence from the f-block elements. Here we show that the uranium(II) metallocene [U(η⁵-C₅ⁱPr₅)₂] and the uranium(III) metallocene [IU(η⁵-C₅ⁱPr₅)₂] can be reduced by potassium graphite in the presence of 2.2.2-cryptand to the uranium(I) metallocene [U(η⁵-C₅ⁱPr₅)₂]^- (1) (C₅ⁱPr₅ = pentaisopropylcyclopentadienyl) as the salt of [K(2.2.2-cryptand)]⁺. An X-ray crystallographic study revealed that 1 has a bent metallocene structure, and theoretical studies and magnetic measurements confirmed that the electronic ground state of uranium(I) adopts a 5f³(7s/6d_z²)¹(6d_x²-y²/6d_xy)¹ configuration. The metal-ligand bonding in 1 consists of contributions from uranium 5f, 6d, and 7s orbitals, with the 6d orbitals engaging in weak but non-negligible covalent interactions. Identification of the oxidation state +1 for uranium expands the range of isolable oxidation states for the f-block elements and potentially signposts a synthetic route to this elusive species for other actinides and the lanthanides.

Multimetallic cooperativity is believed to play a key role in the cleavage of dinitrogen to nitrides (N^3–), but the mechanism remains ambiguous due to the lack of isolated intermediates. Herein, we report the reduction of the complex [K₂{[U^V(OSi(O^tBu)₃)₃]₂(μ-O)(μ-η²:η²-N₂)}], B, with KC₈, yielding the tetranuclear tetranitride cluster [K₆{(OSi(O^tBu)₃)₂U^IV}₃{(OSi(O^tBu)₃)₂U^VI}(μ₄-N)₃(μ₃-N)(μ₃-O)₂], 1, a novel example of N₂ cleavage to nitride by a diuranium complex. The structure of complex 1 is remarkable, as it contains a unique uranium center bound by four nitrides and provides the second example of a trans-N═U^VI═N core analogue of UO₂²⁺. Experimental and computational studies indicate that the formation of the U(IV)/U(VI) tetrauranium cluster occurs via successive one-electron transfers from potassium to the bound N₂^4– ligand in complex B, resulting in N₂ cleavage and the formation of the putative diuranium(V) bis-nitride [K₄{[U^V(OSi(O^tBu)₃)₃]₂(μ-O)(μ-N)₂}], X. Additionally, cooperative potassium binding to the U-bound N₂^4– ligand facilitates dinitrogen cleavage during electron transfer. The nucleophilic nitrides in both complexes are easily functionalized by protons to yield ammonia in 93–97% yield and with excess ¹³CO to yield K¹³CN and KN¹³CO. The structures of two tetranuclear U(IV)/U(V) bis- and mononitride clusters isolated from the reaction with CO demonstrate that the nitride moieties are replaced by oxides without disrupting the tetranuclear structure, but ultimately leading to valence redistribution.

Terminal uranium nitrides have so far proven impossible to isolate by photolysis of azides. Here we report the second ever example of an isolated terminal uranium(VI) nitride. We show that the terminal nitride [NBu₄][U(OSi(O^tBu)₃)₄(N)], 3, can be prepared upon photolysis with UV light of the U(IV) azide analogue. This is achieved by careful tailoring of the azide precursor and of the reaction conditions. Complex 3 is stable under ambient conditions but reacts readily with electrophiles (H⁺ and CO).

The synthesis and reactivity of uranium compounds supported by the tris-tert-butoxysiloxide ligand is surveyed. The multiple binding modes of the tert-butoxysiloxide ligand have proven very well suited to stabilize highly reactive homo- and heteropolymetallic complexes of uranium that have shown an unusual high reactivity towards small molecules such as CO₂, CS₂, chalcogens and azides. Moreover, these ligands have allowed the isolation of dinuclear nitride and oxide bridged complexes of uranium in various oxidation states. The ability of the tris-tert-butoxysiloxide ligands to trap alkali ions in these nitride or oxide complexes leads to unprecedented ligand based and metal based reduction and functionalization of N₂, CO, CO₂ and H₂.

The reactivity of the nitride ligand is increased in complexes of uranium( iv ) when bound by the OSi(O ^t Bu) ₃ ligand as opposed to N(SiMe ₃ ) ₂ , but magnetic exchange coupling is decreased.