Microglia in pediatric brain tumors: The missing link to successful immunotherapy.

Brain tumors are the leading cause of cancer-related mortality in children. Despite the development of immunotherapeutic strategies for adult brain tumors, progress in pediatric neuro-oncology has been hindered by the complex and poorly understood nature of the brain's immune system during early development, a phase that is critical for the onset of many pediatric brain tumors. A defining characteristic of these tumors is the abundance of microglia, the resident immune cells of the central nervous system. In this review, we explore the concept of microglial diversity across brain regions and throughout development and discuss how their maturation stage may contribute to tumor growth in children. We also summarize the current knowledge on the roles of microglia in common pediatric brain tumor entities and provide examples of myeloid-based immunotherapeutic strategies. Our review underscores the importance of microglial plasticity in pediatric brain tumors and its significance for developing effective immunotherapeutic strategies.

Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study.

Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 µM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.

Enantio- and diastereoselective organocatalytic α-alkylation of aldehydes with 3-substituted 2-(bromomethyl)acrylates.

The catalytic direct α-alkylation of aldehydes with 2-(bromomethyl)acrylates has been accomplished, giving rise to α-branched and functionalized aldehydes of high diastereo- and enantiopurity. The influence of the nature of the ester group of the acrylates in reaction stereoselectivity and especially in reactivity is investigated. Optimum conditions implicate the use of phenyl acrylates in conjunction with organocatalyst 8. Application of thus obtained adducts in synthesis is illustrated with a concise stereocontrolled preparation of trisubstituted cyclopentenes.

Brønsted acid assisted regio- and enantioselective direct O-nitroso aldol reaction catalysed by alpha,alpha-diphenylprolinol trimethylsilyl ether.

In the presence of p-nitrobenzoic acid, the O-nitroso aldol reaction of nitrosobenzene with enolisable aldehydes may be promoted by commercially available alpha,alpha-diphenylprolinol trimethylsilyl ether. The reaction proceeds with good yields and essentially complete enantioselectivity, with catalyst loadings in the 5-10 mol % range. The resulting alpha-oxyaldehyde adducts may be transformed in situ into alpha-oxyimines, which provide 1,2-amino alcohols upon treatment with Grignard reagents, in good overall yield (45-59%) and with typical diastereomeric ratios > or = 95:5.

A 4-hydroxypyrrolidine-catalyzed mannich reaction of aldehydes: control of anti-selectivity by hydrogen bonding assisted by Brønsted acids.

An anti-selective Mannich reaction of aldehydes with N-sulfonyl imines has been developed by using a 4-hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the alpha-substituent of the pyrrolidine, the 4-hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde-derived imines, which have rarely been employed in previously reported enamine-based anti-Mannich reactions. Additionally, both N-tosyl and N-nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N-deprotection the corresponding beta-amino acids and beta-amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine-based reactions.