Green Oxidation of Ketones to Lactones with Oxone in Water

Cyclic ketones were quickly and quantitatively converted to 5-, 6- and 7-membered lactones, very important synthons, by treatment with Oxone, a cheap, stable, and non-pollutant oxidizing reagent, in 1M NaH2PO4/Na2HPO4 water solution (pH 7). Under such simple and green conditions, no hydroxyacid was formed thus making unnecessary the adoption of more com-plex and non-ecofriendly procedures previously developed to avoid lactone hydrolysis. With some changes, the method was successfully applied also to water insoluble ketones such as adamantanone, acetophenone, 2-indanone and challenging cy-cloheptanone

Pyrrolidinyl benzofurans and benzodioxanes: Selective α4β2 nicotinic acetylcholine receptor ligands with different activity profiles at the two receptor stoichiometries

A series of racemic benzofurans bearing N-methyl-2-pyrrolidinyl residue at C(2) or C(3) has been synthesized and tested for affinity at the α4β2 and α3β4 nicotine acetylcholine receptors (nAChRs). As previously reported for the benzodioxane based analogues, hydroxylation at proper position of benzene ring results in high α4β2 nAChR affinity and α4β2 vs. α3β4 nAChR selectivity. 7-Hydroxy-N-methyl-2-pyrrolidinyl-1,4-benzodioxane (2) and its 7- and 5-amino benzodioxane analogues 3 and 4, which are all α4β2 nAChR partial agonists, and 2-(N-methyl-2-pyrrolidinyl)-6-hydroxybenzofuran (12) were selected for functional characterization at the two α4β2 stoichiometries, the high sensitivity (α4)2(β2)3 and the low sensitivity (α4)3(β2)2. The benzene pattern substitution, which had previously been found to control α4β2 partial agonist activity and α4β2 vs. α3β4 selectivity, proved to be also involved in stoichiometry-selectivity. The 7-hydroxybenzodioxane derivative 2 selectively activates (α4)2(β2)3 nAChR, which cannot be activated by its 5-amino analogue 4. A marginal structural modification, not altering the base pyrrolidinyl benzodioxane scaffold, resulted in opposite activity profiles at the two α4β2 nAChR isoforms providing an interesting novel case study

4-, 5-, 6-, and 7-Hydroxybenzofuran: a unified strategy for a two-step synthesis of versatile benzofuranic building blocks

Over several decades, many different strategies have been reported to prepare 4-, 5- , 6-, and 7- hydroxybenzofuran (HBF), which are very important synthetic intermediates. Interested in addition of their 2- lithiated O-protected derivatives to transient 1-pyrroline as a straightforward way to nicotinoids, we have developed a unique two-step procedure to obtain 4-, 5- , 6-, and 7-HBF from 2,6-, 2,5-, 2-4- and 2,3- dihydroxyacetophenone, respectively, by conversion into 4-, 5-, 6- and 7-hydroxybenzofuranone and successive reduction of these latter with lithium borohydride. On the basis of the overall yields, the number of steps and the availability of the starting materials, such a synthetic strategy can be advantageously compared with the literature methods, here briefly reviewed, developed to synthesize the four HBFs.(piture presented

Selective potentiation of the (α4)3(β2)2 nicotinic acetylcholine receptor response by NS9283 analogues

NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4)3(β2)2 nicotinic acetylcholine receptors (nAChR). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4-α4 subunit interface present in the (α4)3(β2)2 nAChR. However, there is currently a lack of structure activity relationships (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the α4-α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4)3(β2)2 nAChRs vs nAChR subtypes (α4)2(β2)3, α5α4β2 and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4)3(β2)2 nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl (4), 4-cyanophenyl (10), and N-formyl-4-piperidinyl (20) showed the same efficacy as NS9283, although with lower potency. Molecular dynamic simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the α4-α4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side

A Photoactivatable Version of Ivabradine Enables Light-Induced Block of HCN Current In Vivo

Therapeutic drugs, whose bioactivity is hindered by a photoremovable cage, offer the advantage of spatiotemporal confinement of their action to the target diseased tissue with improved bioavailability and efficacy. Here, we have applied such an approach to ivabradine (IVA), a bradycardic agent indicated for angina pectoris and heart failure, acting as a specific HCN channel blocker. To overcome the side effects due to its poor discrimination among HCN channel subtypes (HCN1–4), we prepared a caged version of IVA linked to a photocleavable bromoquinolinylmethyl group (BHQ-IVA). We show that upon illumination with blue light (440 nm), BHQ-IVA releases active IVA that blocks HCN channel currents in vitro and exerts a bradycardic effect in vivo. Both BHQ-IVA and the cage are inactive. Caging is stable in aqueous medium and in the dark, and it does not impair aqueous solubility and cell permeation, indispensable for IVA activity. This approach allows for bypassing the poor subtype-specificity of IVA, expanding its prescription to HCN-related diseases besides cardiac

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Subnanomolar Affinity and Selective Antagonism at α7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624)

Modifications of the cationic head and the ethylene linker of 2-(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective α9*-nAChR antagonism devoid of any effect on the α7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing α7-nAChR antagonism without abolishing α9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (31), resulted in higher and more selective α7-nAChR affinity. Hybridization of this modification with the constraint of the 2-triethylammoniumethyloxy portion into (R)-N,N-dimethyl-3-pyrrolidiniumoxy substructure, previously reported as the best modification for the α7-nAChR affinity of MG624 (2), was a winning strategy. The resulting hybrid 33 had a subnanomolar α7-nAChR affinity and was a potent and selective α7-nAChR antagonist, producing at the α7-, but not at the α9*-nAChR, a profound loss of subsequent ACh function

Fibroma ossificante dei seni paranasali: diagnosi e management

Le lesioni fibro-ossee benigne raramente colpiscono i seni paranasali e sono suddivise in 3 entità: osteoma, displasia fibrosa e fibroma ossificante. Questi presentano simili caratteristiche cliniche, radiologiche e istologiche ma hanno un comportamento diverso. Il fibroma ossificante, in particolare la variante istologica giovanile, può presentare un comportamento aggressivo con un alto rischio di recidiva se rimosso in modo incompleto. Lo scopo dello studio è quello di paragonare il comportamento clinico del fibroma ossificante con quello delle altre lesioni fibro-ossee; di evidenziare un eventuale comportamento differente tra i vari sottotipi istologici; di descrivere i vantaggi, i limiti e i risultati della chirurgia endoscopica endonasale rispetto ai dati presenti in letteratura. Abbiamo analizzato retrospettivamente 11 pazienti affetti da fibroma ossificante naso-sinusale e trattati in un centro ospedaliero di terzo livello. Tutti i pazienti sono stati sottoposti a TC. La RM è stata eseguita in caso di coinvolgimento del basicranio o in caso di recidiva. Una biopsia pre-operatoria è stata effettuata nei casi in cui la massa era raggiungibile per via endoscopica. Un paziente è stato sottoposto a embolizzazione pre-operatoria ed ha riportato una cecità monolaterale al termine della procedure. In base alla localizzazione, l’exeresi del tumore è stata eseguita con un approccio endoscopico (7 pazienti), esterno (3), combinato (1). Istologicamente 5 pazienti hanno riportato un sottotipo convenzionale, 5 la variante giovanile psammomatoide associata in un caso a cisti aneurismatica ossea, e un paziente la variante giovanile trabecolare. Tre pazienti affetti dalla variante istologica giovanile psammomatoide hanno presentato un’invasione del basicranio e sono stati sottoposti ad exeresi subtotale per via endoscopica che ha richiesto in seguito, a causa di un aumento di volume del residuo, un secondo intervento per via transbasale. I reperti clinici, radiologici e istologici dovrebbero essere considerati insieme per una accurata diagnosi differenziale tra le lesioni fibro-ossee. Ulteriori studi sono necessari per concludere se la localizzazione e l’estensione del fibroma ossificante al momento della diagnosi sono più importanti della variante istologica. L’approccio endoscopico è la prima opzione nella maggior parte dei casi anche se in alcuni selezionati pazienti l’approccio esterno risulta ancora necessario

Modular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery

Fragment-based drug discovery (FBDD) is a key strategy employed in the hit-to-lead phase of pharmaceutical development. The rate limiting step of this process is often identifying and optimising synthetic chemistry suitable for fragment elabora-tion, especially in 3-dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of 2-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilising nine bifunction-al building blocks that explore a range of vectors in 3-D. The building blocks comprise: (i) rigid sp3-rich bicyclic cyclopro-pane-based structures to fix the vectors, and (ii) two synthetic handles – a protected cyclic amine and a cyclopropyl N-methyliminodiacetic acid (MIDA) boronate. To validate our approach, we present: (i) multi-gram scale synthesis of each 3-D building block; (ii) Suzuki-Miyaura cross-coupling reactions of the cyclopropyl BMIDA functionality with aryl bromides; (iii) N-functionalisation (via commonplace medicinal chemistry toolkit reactions) of arylated products to deliver 3-D lead-like compounds. Each building block accesses a distinct 3-D exit vector, as shown by analysis of the lowest energy confor-mations of lead-like molecules using RDKit, and by X-ray crystallography of pyrimidine methanesulfonamide derivatives. Since the synthetic methodology is established in advance of fragment screening and utilises robust chemistry, the elabora-tion of fragment hits in 3-D for biochemical screening can be achieved rapidly. To provide proof-of-concept, starting from the drug Ritlecitinib, the development of inhibitors of Janus kinase 3 (JAK3) around a putative pyrrolopyrimidine 2-D frag-ment hit was explored, streamlining the discovery of a novel and selective JAK3 inhibitor with IC50 = 69 nM