Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta peptide production measurements by specific in vitro assays (gamma-secretase Cell Free assay and Cell Based assay on HEK 293 APP transfected cells) and, on the other hand, pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.     

Photo-induced pyridine substitution in cis-[Ru(bpy)(2)(py)(2)]Cl(2): a snapshot by time-resolved X-ray solution scattering

Determination of transient structures in light-induced processes is a challenging goal for time-resolved techniques. Such techniques are becoming successful in detecting ultrafast structural changes in molecules and do not require the presence of probe-like groups. Here, we demonstrate that TR-WAXS (Time-Resolved Wide Angle X-ray Scattering) can be successfully employed to study the photochemistry of cis-[Ru(bpy)(2)(py)(2)]Cl(2), a mononuclear ruthenium complex of interest in the field of photoactivatable anticancer agents. TR-WAXS is able to detect the release of a pyridine ligand and the coordination of a solvent molecule on a faster timescale than 800 ns of laser excitation. The direct measurement of the photodissociation of pyridine is a major advance in the field of time-resolved techniques allowing detection, for the first time, of the release of a multiatomic ligand formed by low Z atoms. These data demonstrate that TR-WAXS is a powerful technique for studying rapid ligand substitution processes involving photoactive metal complexes of biological interest.     

Os(bpy)2(CO)(enIA)][OTf]2: a novel sulfhydryl-specific metal-ligand complex

The synthesis and physical-chemical characterization of the metal-ligand complex [Os(bpy)2(CO)(enIA)][OTf]2 (where enIA = ethylenediamine iodoacetamide) with a sulfhydryl-specific functional group is described. The UV and visible absorption and luminescence emission, including lifetime and steady-state anisotropy, are reported for the free probe and the probe covalently linked to two test proteins. The spectroscopic properties of the probe are unaffected by chemical modification and subsequent covalent linkage to the proteins. The luminescence lifetime in aqueous buffer is approximately 200 ns and the limiting anisotropy is greater than 0.125, suggesting a potentially useful probe for biophysical investigations.     

Dipyridylketone as a versatile ligand precursor for new cationic heteroleptic cyclometalated iridium complexes

Three new bis-cyclometalated iridium(III) complexes, of general formula [Ir(2-phenylpyridine)(2)(L)](+), are reported. The compounds contain a dipyridine-type ligand (L) derived from di-2-pyridylketone (dipyridin-2-ylmethanol, 2,2'-(hydrazonomethylene)dipyridine and 3-hydroxy-3,3-di(pyridine-2-yl)propanenitrile) and were synthesized through two different reaction pathways. The alternative synthetic pathway herein proposed, namely the direct reactions on the complex [Ir(2-phenylpyridine)(2)(2,2'-dipyridylketone)](+), overcame the inconveniences encountered with the standard reaction between the dimeric precursor [Ir(2-phenylpyridine)(2)(μ-Cl)](2) and the ancillary ligands (L). The photophysical characterization of the iridium complexes reveals that modifications on the ancillary ligand introduce large changes in the photophysical behaviour of the complexes. High emission quantum yield is associated with the presence of a saturated carbon between the two pyridyl moieties: [Ir(2-phenylpyridine)(2)(2,2'-dipyridylketone)](+) and [Ir(2-phenylpyridine)(2)(2,2'-(hydrazonomethylene)dipyridine)](+) are extremely low emissive, while [Ir(2-phenylpyridine)(2)(dipyridin-2-ylmethanol)](+) and [Ir(2-phenylpyridine)(2)(3-hydroxy-3,3-di(pyridine-2-yl)propanenitrile)](+) are good photoemitters. DFT and TD-DFT calculations confirmed the mixed LC/MLCT character of the excited states involved in the absorption and emission processes and highlighted the role of the π-conjugation between the two subunits of the ancillary ligand in determining the nature of the LUMO.     

The Richest Collection of Tautomeric Polymorphs: The Case of 2‐Thiobarbituric Acid

Five new polymorphs and one hydrated form of 2‐thiobarbituric acid have been isolated and characterised by solid‐state methods. In both the crystalline form II and in the hydrate form, the 2‐thiobarbituric molecules are present in the enol form, whereas only the keto isomer is present in crystalline forms I (reported in 1967 by Calas and Martinex), III , V and VI . In form IV , on the other hand, a 50:50 ordered mixture of enol/keto molecules is present. All new forms have been characterised by single‐crystal X‐ray diffraction, 1D and 2D (¹H, ¹³C, and ¹⁵N) solid‐state NMR spectroscopy, Raman spectroscopy and X‐ray powder diffraction at variable temperature. It has been possible to induce keto–enol conversion between the forms by mechanical methods. The role of hydrogen‐bond interactions in determining the relative stability of the polymorphs and as a driving force in the conversions has been ascertained. To the best of the authors’ knowledge, the 2‐thiobarbituric family of crystal forms represents the richest collection of examples of tautomeric polymorphism so far reported in the literature.     

Non-covalent conjugates between cationic polyamino acids and GdIII chelates: a route for seeking accumulation of MRI-contrast agents at tumor targeting sites

Three novel Gd chelates containing on their external surface pendant phosphonate and carboxylate groups, which promote the interaction with the positively charged groups of polyornithine and polyarginine, have been synthesized. Their solution structures have been assessed on the basis of 1H- and 31P-NMR spectra of the Eu and Yb analogues. A thorough investigation of the relaxometric (1H and 17O) properties of the Gd chelates has been carried out and the observed relaxivities have been accounted for the sum of three contributions arising from water molecules in the first, second, and outer coordination layers, respectively. It has been found that the occurrence of a tight second coordination coating renders the dissociation of the water molecule directly coordinated to the Gd ion more difficult. The binding interactions between the negatively charged Gd chelates and the positively charged groups of polyornithine (ca. 140 residues) and polyarginine (ca. 204 residues) have been evaluated by means of the proton relaxation enhancement (PRE) method. Although the binding interaction decreases markedly in the presence of competitive anions in the solution medium, the affinity is strong enough that in blood serum it is possible to meet the conditions where most of the chelate is bound to the polyamino acid substrate. On this basis one may envisage a novel route for a MRI location of tumors as it is known that positively charged polyamino acids selectively bind to tumors having a greater negative charge than non-tumor cells.     

Exploring synthetic pathways to cationic heteroleptic cyclometalated iridium complexes derived from dipyridylketone

Reactions between 2,2'-dipyridylketone (L1) and different amines gave a series of iminic ligands, and their chemical reductions produced the related amines. The organic ligands were employed in the syntheses of the corresponding new phosphorescent six-member ring bis-cyclometalated heteroleptic iridium(III) complexes of general formula [Ir(ppy)(2)(L)](+) (ppy = 2-phenylpyridine), namely IrLn. The metal complexes containing N-(dipyridin-2-ylmethylene)butan-1-amine (IrL2), N-(dipyridin-2-ylmethyl)butan-1-amine (IrL5), N-(dipyridin-2-ylmethyl)butane-1,4-diamine with amino groups protected by Boc (IrL6-Boc) and TFA (IrL6-TFA), and N-(dipyridin-2-ylmethyl)-N-methylbutan-1-amine (IrL8) were characterized and their electronic and spectroscopic properties interpreted by DFT calculations. Organoiridium complexes containing amines and imines were found to have high and low photoemission quantum yields, respectively, and their features rationalized by quantum mechanic calculations. Some of these complexes show reasonable quantum yields (up to 13%), long lifetime (up to 2.3 μs) and high stability. Complementary and alternative synthetic pathways to get cationic heteroleptic cyclometalated Ir complexes bearing a tethered primary amino group have been explored with the aim to obtain organometallic phosphorescent derivatives suitable for surface functionalization.