Highly Enantioselective Iridium(I)-Catalyzed Hydrocarbonation of Alkenes: A Versatile Approach to Heterocyclic Systems Bearing Quaternary Stereocenters.

We report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five-, six- and seven-membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non-covalent interactions as key factors to control the enantioselectivity.

Discovery of a Necroptosis Inhibitor Improving Dopaminergic Neuronal Loss after MPTP Exposure in Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent form of regulated cell death mediated by the concerted action of receptor-interacting protein 3 (RIP3) and the pseudokinase mixed lineage domain-like protein (MLKL). It is also usually dependent on RIP1 kinase activity, influenced by further cellular clues. Importantly, necroptosis appears to be strongly linked to several neurodegenerative diseases, including PD. Here, we aimed at identifying novel chemical inhibitors of necroptosis in a PD-mimicking model, by conducting a two-step screening. Firstly, we phenotypically screened a library of 31 small molecules using a cellular model of necroptosis and, thereafter, the hit compound effect was validated in vivo in a sub-acute 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) PD-related mouse model. From the initial compounds, we identified one hit-Oxa12-that strongly inhibited necroptosis induced by the pan-caspase inhibitor zVAD-fmk in the BV2 murine microglia cell line. More importantly, mice exposed to MPTP and further treated with Oxa12 showed protection against MPTP-induced dopaminergic neuronal loss in the SN and striatum. In conclusion, we identified Oxa12 as a hit compound that represents a new chemotype to tackle necroptosis. Oxa12 displays in vivo effects, making this compound a drug candidate for further optimization to attenuate PD pathogenesis.

Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation.

Necroptosis is a regulated form of necrosis, which may be critical in the pathogenesis of neurodegenerative diseases. Neuroinflammation, characterized by the activation of glial cells such as microglia, is closely linked with neurodegenerative pathways and constitutes a major mechanism of neural damage and disease progression. Importantly, inhibition of necroptosis results in disease improvement, unveiling an alternative approach for therapeutic intervention. In the present study, we screened a small library of new molecules, potentially inhibitors of necroptosis, using two cellular models of necroptosis. A new oxazolone, Oxa12, reduced tumour necrosis factor α (TNF-α)-induced necroptosis in mouse L929 fibrosarcoma cells. Notably, Oxa12 strongly inhibited zVAD-fmk-induced necroptosis in murine BV2 microglial cells. Moreover, Oxa12 blocked phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and interfered with necrosome complex formation, indicating that Oxa12 targets components upstream of MLKL. In fact, in silico molecular docking studies revealed that Oxa12 is occupying a region similar to the 1-aminoisoquinoline type II kinase inhibitor inside the receptor-interacting protein 1 (RIP1) kinase domain. Finally, in microglial cells, Oxa12 attenuated zVAD-fmk- and lipopolysaccharide (LPS)-induced inflammatory processes, as revealed by a marked decrease of TNF-α and/or IL-1ß expression. More specifically, Oxa12 negatively targeted c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, as well as NF-κB activation. Overall, we identified a strong lead inhibitor of necroptosis that is also effective at reducing inflammation-associated events. Oxa12 is a promising candidate molecule for further development to target disease states dependent on RIP kinase activity.

Valorization of Oleuropein via Tunable Acid-Promoted Methanolysis.

The acid-promoted methanolysis of oleuropein was studied using a variety of homogeneous and heterogeneous acid catalysts. Exclusive cleavage of the acetal bond between the glucoside and the monoterpene subunits or further hydrolysis of the hydroxytyrosol ester and subsequent intramolecular rearrangement were observed upon identification of the most efficient catalyst and experimental conditions. Furthermore, selected conditions were tested using oleuropein under continuous flow and using a crude mixture extracted from olive leaves under batch. Formation of (-)-methyl elenolate was also observed in this study, which is a reported precursor for the synthesis of the antihypertensive drug (-)-ajmalicine.

Synthesis of γ-pyrones via decarboxylative condensation of ß-ketoacids.

ABSTRACT: This manuscript describes the convergent synthesis of aryl- and alkyl-disubstituted γ-pyrones from ß-ketoacids. The reaction proceeds in the presence of trifluoromethanesulfonic anhydride via an unprecedented decarboxylative auto-condensation of the starting material. Herein, the scope and limitations of this transformation are reported.

Direct synthesis of γ-pyrones by electrophilic condensation of ß-ketoesters.

Triflic anhydride is a versatile electrophile that is able to activate poor nucleophiles. Herein, we show that readily available ß-keto esters are activated by Tf2O furnishing γ-pyrones. Mechanistic studies suggest that this transformation proceeds via a double triflation, formation of an oxocarbenium intermediate and dealkylation promoted by a crucial nitrile additive.

Bridging C-H Activation: Mild and Versatile Cleavage of the 8-Aminoquinoline Directing Group.

8-Aminoquinoline has emerged as one of the most powerful bidentate directing groups in history of C-H activation within the last decade. However, cleavage of its robust amide bond has shown to be challenging in several cases, thus jeopardizing the general synthetic utility of the method. To overcome this limitation, we herein report a simple oxidative deprotection protocol. This transformation rapidly converts the robust amide to a labile imide, allowing subsequent cleavage in a simple one-pot fashion to rapidly access carboxylic acids or amides as final products.

Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids.

A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.

"Click and go": simple and fast folic acid conjugation.

Folic acid targeting by functionalization of the terminal γ-carboxylic acid is one of the most important strategies to selectively deliver chemotherapeutics and dyes to cancer cells which overexpress folate receptors. However, conjugation of folic acid is limited by its unique solubility and by selectivity issues imposing the need for expensive preparative reverse-phase chromatographic purification to isolate γ-folate conjugates. Herein is provided a novel synthetic tool for the synthesis of new folic acid conjugates with excellent γ-purity based on strain-promoted alkyne-azide cycloadditions with a γ-folate-cyclooctyne conjugate 3. To demonstrate the potential of this methodology several new folate conjugates were synthesized with high γ-purity and without using any type of chromatographic purification by reacting conjugate 3 with several fluorescent probes, polymers and siliceous materials bearing azide. In addition, the cycloaddition reaction between conjugate 3 and an azido-derived fluorescent dye was successfully performed in cellular media leading to an increase of fluorescence in the cells which overexpress folate receptors (NCI-H460).

Excited-state proton transfer of fluorescein anion as an ionic liquid component.

Fluorescent ionic liquids (FILs) incorporating the fluorescein anion have been prepared by anion exchange of the parent quaternary ammonium chloride (Quat(+)Cl(-)) ionic liquid. By controlling the molar ratio of fluorescein to Quat(+)Cl(-), ionic liquids incorporating different prototropic forms of fluorescein were prepared. The 1:1 molar ratio ionic liquid (FIL1) is essentially composed of monoanionic fluorescein, while dianionic fluorecein is predominant in the FIL with a 1:2 molar ratio (FIL2). The fluorescence excitation spectrum of FIL2 is markedly different from its absorption spectrum. Absorption features the fluorescein dianion, while the excitation spectrum is exclusively due to the monoanion. In FIL1, the absorption and excitation spectra are both characteristic of the monoanion. In both FILs, emission of the dianion is observed upon excitation of the monoanion. This unusual behavior is interpreted in the context of a fast deprotonation of the monoanion in the excited state. The presence of residual water in the ionic liquid is important for the proton transfer process. By lowering the pH of FIL1, the transient proton transfer is inhibited, and the emission of the monoanion could be observed. The FILs have completely different spectroscopic properties from solvated fluorescein in Quat(+)Cl(-), where the prototropic equilibrium is shifted toward the neutral forms.