Sulfone-based human liver pyruvate kinase inhibitors - Design, synthesis and in vitro bioactivity.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC50 value of 0.07 µM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors.

Turn-on Fluorescent Biosensors for Imaging Hypoxia-like Conditions in Living Cells.

We present the synthesis, photophysical properties, and biological application of nontoxic 3-azo-conjugated BODIPY dyes as masked fluorescent biosensors of hypoxia-like conditions. The synthetic methodology is based on an operationally simple N═N bond-forming protocol, followed by a Suzuki coupling, that allows for a direct access to simple and underexplored 3-azo-substituted BODIPY. These dyes can turn on their emission properties under both chemical and biological reductive conditions, including bacterial and human azoreductases, which trigger the azo bond cleavage, leading to fluorescent 3-amino-BODIPY. We have also developed a practical enzymatic protocol, using an immobilized bacterial azoreductase that allows for the evaluation of these azo-based probes and can be used as a model for the less accessible and expensive human reductase NQO1. Quantum mechanical calculations uncover the restructuration of the topography of the S1 potential energy surface following the reduction of the azo moiety and rationalize the fluorescent quenching event through the mapping of an unprecedented pathway. Fluorescent microscopy experiments show that these azos can be used to visualize hypoxia-like conditions within living cells.

Hígado agudo graso del embarazo: reporte de caso / Acute fatty liver of pregnancy: case report

El hígado graso del embarazo es una patología poco frecuente en la especialidad obstétrica, cuyo diagnóstico se realiza basado en los criterios de Swansea, muchas veces es un diagnóstico que se realiza por exclusión; usualmente se presenta entre las semanas 30 y 35 del embarazo, y la cura definitiva se realiza con la interrupción expedita del mismo; con una tasa de recuperación casi del 100% si se realiza la interrupción oportuna y una tasa de mortalidad materno fetal actual del 10%. Es importante estar atentos a la ganancia ponderal de la embarazada durante el control prenatal, la epigastralgia, y los signos clínicos asociados a hipoglicemia(AU)

Fatty liver of pregnancy is a rare pathology in obstetrics, whose diagnosis is made based on the Swansea criteria, many times it is a diagnosis that is made by exclusion; It usually occurs between weeks 30 and 35, and the definitive cure is carried out with the expeditious interruption of pregnancy; with a recovery rate of almost 100% if timely interruption is made and a current maternal-fetal mortality rate of 10%. It is important to be attentive to the weight gain of the pregnant woman during prenatal control, epigastric pain, and clinical signs associated with hypoglycemia

Alcohol Etherification via Alkoxy Radicals Generated by Visible-Light Photoredox Catalysis.

A mechanistically divergent method is described that, employing a commercially available hypervalent iodine(III) reagent, generates alkoxy radicals from 1°, 2°, and 3° alcohols and allows their use in the functionalization of C(sp3)-H and C(sp2)-H bonds. This visible-light photoredox catalysis produces alkyl ethers via 1,5/6-hydrogen atom transfer or aryl ethers via 1,5-addition. This mild methodology provides a practical strategy for the synthesis of acetals, orthoesters, tetrahydrofurans, and chromanes.

Evaluation of Empirical Pretreatment Assessments for Developing Treatments for Packing in Pediatric Feeding Disorders.

A significant problem among children with feeding disorders is packing (i.e., pocketing or holding accepted food in the mouth), which could hinder successful treatment. Previous research has identified effective treatments to reduce packing; however, an assessment model to guide treatment decisions is lacking. In the present study, we used a multielement design to identify conditions under which low levels of packing occurred for 4 children with feeding disorders. Results were used to empirically inform treatment selection to decrease packing for 3 children. Assessments indicated that packing was related to texture, food preference, or response effort and subsequently informed individualized treatments, which led to decreased levels of packing. Results suggest that this model may be useful in the design of treatment packages for children who engage in packing at clinically problematic levels.

Palladium-Catalyzed Benzylic Arylation of Pyridylmethyl Silyl Ethers: One-Pot Synthesis of Aryl(pyridyl)methanols.

An efficient palladium-catalyzed direct arylation of pyridylmethyl silyl ethers with aryl bromides is described. A Pd(OAc)2/NIXANTPHOS-based catalyst provides aryl(pyridyl)methyl alcohol derivatives in good to excellent yields (33 examples, 57-100% yield). This protocol is compatible with different silyl ether protecting groups, affording either the protected or the free alcohols in an effective one-pot process. The scalability of the reaction is demonstrated.

Synthesis of oxaspiranic compounds through [3 + 2] annulation of cyclopropenones and donor­acceptor cyclopropanes.

The Sc(OTf)3-catalyzed [3 + 2]-annulation reaction between cyclopropenones and donor­acceptor cyclopropanes is described. The process leads directly to the formation of 4-oxaspiro[2.4]hept-1-ene derivatives in good to excellent reaction yields. Density functional theory calculations suggest that the [3 + 2]-annulation pathway is strongly preferred over the possible [3 + 3]-process.

The photochemical reaction of vinylaziridines and vinylazetidines with chromium(0) and molybdenum(0) (Fischer) carbene complexes.

The [5+2] and [6+2] cycloaddition reactions of vinylaziridines and vinylazetidines with ketenes generated photochemically from chromium(0) and molybdenum(0) Fischer carbene complexes have been investigated. These processes constitute a straightforward and efficient route to azepanones and azocinones, respectively. The peculiar electronic properties of the metalated ketenes allow for the introduction of electron-rich substituents in the final cycloadducts, a difficult task using conventional organic chemistry procedures. The versatility of the process is demonstrated by using Cr(0) Fischer bis(carbene) complexes as metalated bis(ketene) precursors. These species produce tethered bis(azepanone)s in a single step under mild reaction conditions. Density functional theory calculations point to a stepwise reaction pathway through the initial nucleophilic attack of the nitrogen atom of the aziridine on the metalated ketene, followed by ring closure of the zwitterionic intermediate formed.

Regio- and diastereoselective stepwise [8 + 3]-Cycloaddition reaction between tropone derivatives and donor-acceptor cyclopropanes.

A novel SnCl4-catalyzed [8 + 3]-cycloaddition reaction between tropone derivatives and donor-acceptor aminocyclopropanes is described. The process leads to the formation of amino-substituted tetrahydrocyclohepta[b]pyrans with complete regio- and diastereoselectivity. Density functional theory calculations suggest that the cycloaddition occurs stepwise through an aromatic zwitterionic intermediate.

Regioselective and stepwise [8 + 2] cycloaddition reaction between alkynyl-Fischer carbene complexes and tropothione.

The formal [8 + 2] cycloaddition reaction between alkynyl Fischer carbene complexes and tropothione leads to the regioselective formation of novel 3aH-cyclohepta[b]thiophene carbene complexes. Computational DFT calculations indicate that the process proceeds stepwise via antiaromatic zwitterionic intermediates.