Tribromide enabled step-up generation of spirolactams from esters employing oxidative dearomatization of arenols.

Synthetically challenging spirolactams were developed in good yields and regio-selectivity through a step-up oxidative dearomatization of easily accessible arenols tethered to esters in the presence of quaternary ammonium tribromide as an economic oxidant and amines. The reaction mechanism associated with this unprecedented dearomative lactamisation has been forecasted with a series of controlled experiments and DFT studies.

BF·EtO-assisted synthesis of sulfinylated spiro[5.5]trienones from biaryl ynones.

Sulfinyls are valuable structural moieties used for developing synthetically new pharmaceuticals and agrochemicals. Herein, we disclose a straightforward synthesis of sulfinylated spiro[5.5]trienones proceeding an unprecedented BF·EtO-promoted spirocyclization of biaryl ynones.

Protein semisynthesis underscores the role of a conserved lysine in activation and desensitization of acid-sensing ion channels.

Acid-sensing ion channels (ASICs) are trimeric ion channels that open a cation-conducting pore in response to proton binding. Excessive ASIC activation during prolonged acidosis in conditions such as inflammation and ischemia is linked to pain and stroke. A conserved lysine in the extracellular domain (Lys211 in mASIC1a) is suggested to play a key role in ASIC function.

Sustainable Organic Photocatalysis for Site-Selective Hydrazocoupling of Electron-Rich Arenes.

An efficient photocatalytic - and selective amination and aminative dearomatization of phenols, naphthols, and anilines with azodicarboxylates was developed using riboflavin tetraacetate (RFTA) as an organic photocatalyst. The site selectivity was controlled using tetrabutylammonium bromide (TBAB), which also acts as a phase transfer catalyst. The reaction conditions are simple and mild, giving high regioselectivity with good to excellent yields.

Visible Light Promoted Brominative Dearomatization of Biaryl Ynones to Spirocycles.

Bromine induced spiro cyclization of biaryl ynones facilitated the synthesis of spiro[5,5]trienones suitable for extended functionality at the C(3') position. Herein, a step-economic photo-oxidative brominative carbannulation of biaryl ynones employing ammonium bromide and riboflavin tetraacetate (RFTA) has been developed. The reactivity between distal phenyl C-H activated -annulation and dearomative -annulation is well exemplified.

Riboflavin Photocatalyzed Dearomative Spiro-Etherification of Naphthols.

The dearomative spiro-etherification of naphthols is achieved using catalytic amounts of riboflavin tetracetate (RFTA) as a photosensitizer and molecular oxygen as a terminal oxidizing agent under blue light (440 nm) irradiation in the presence of acid. The presence of acid increases the photooxidation power of RFTA and facilitates the dearomatization reaction.

Dissecting the contributions of membrane affinity and bivalency of the spider venom protein DkTx to its sustained mode of TRPV1 activation.

The spider venom protein, double-knot toxin (DkTx), partitions into the cellular membrane and binds bivalently to the pain-sensing ion channel, TRPV1, triggering long-lasting channel activation. In contrast, its monovalent single knots membrane partition poorly and invoke rapidly reversible TRPV1 activation. To discern the contributions of the bivalency and membrane affinity of DkTx to its sustained mode of action, here, we developed diverse toxin variants including those containing truncated linkers between individual knots, precluding bivalent binding.

Temperature-Controlled Chemoselective Synthesis of Multisubstituted 4-Alkynyl/ 4-Alkenyl Coumarins.

A temperature-controlled facile synthesis of multisubstituted 4-alkynyl/ 4-alkenyl coumarins with a metal salt cascade approach is reported. HO serves both as a nucleophile and hydrogen source. The presence of metal salt facilitates the reduction of alkyne.

Site-Specific Fluorescent Labeling of the Cysteine-Rich Toxin, DkTx, for TRPV1 Ion Channel Imaging and Membrane Binding Studies.

Peptide toxins secreted by venomous animals bind to mammalian ion channel proteins and modulate their function. The high specificity of these toxins for their target ion channels enables them to serve as powerful tools for ion channel biology. Toxins labeled with fluorescent dyes are employed for the cellular imaging of channels and also for studying toxin-channel and toxin-membrane interactions.

Gold(I)-Catalyzed Synthesis of Heterocycles via Allene Oxide from Propargylic Alcohols.

A new mechanistic pathway of propargylic alcohol activation by gold(I) catalysis has been proposed toward the efficient synthesis of N-protected pyrroles, 5,6-dihydropyridin-3(4)-ones from N-protected 5-aminopent-2-yn-1-ol, and 5-aminopent-2-yn-1-ol. Control experiments support that the reaction proceeded via the neighboring group participation of the oxygen atom of propargylic alcohol to form an allene oxide intermediate where the nucleophilic heteroatom attacks intramolecularly. Further, this methodology is successfully extrapolated toward the atom-economic synthesis of hydroxyalkyl indoles and benzofurans.

P2X2 receptor subunit interfaces are missense variant hotspots, where mutations tend to increase apparent ATP affinity.

Background And Purpose: P2X receptors are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding to their large extracellular domain. The seven known P2X subtypes can assemble as homotrimeric or heterotrimeric complexes and contribute to numerous physiological functions, including nociception, inflammation and hearing. The overall structure of P2X receptors is well established, but little is known about the range and prevalence of human genetic variations and the functional implications of specific domains.

Stereoselective Synthesis of Oxacycles via Ruthenium-Catalyzed Atom-Economic Coupling of Propargyl Alcohols and Michael Acceptors.

Synthesis of β-hydroxyenones and its application toward development of tetrahydro-4-pyran-4-one in an atom-economic fashion is limited. This manuscript describes a ruthenium-catalyzed atom-economic coupling of pent-2-yne-1,5-diols and Michael acceptors as an efficient route for the synthesis of β-hydroxyenones with excellent yields and high regioselectivity. The β-hydroxyenones further undergo a 6- cyclization under acid-catalyzed conditions to deliver the tetrahydro-4-pyran-4-ones with high diastereoselectivity.

Synthetic Attempts Towards Eminent Anti-viral Candidates of SARS-CoV.

Severe Acute Respiratory Syndrome (SARS) aka SARS-CoV spread over southern China for the first time in 2002-2003 and history repeated again since last year and took away lives of more than two million people so far. On March 11, 2020 COVID-19 outbreak was officially declared as pandemic by World Health Organization (WHO). The entire world united to fight back against this ultimate destruction.

Ion channel engineering using protein trans-splicing.

Conventional site-directed mutagenesis and genetic code expansion approaches have been instrumental in providing detailed functional and pharmacological insight into membrane proteins such as ion channels. Recently, this has increasingly been complemented by semi-synthetic strategies, in which part of the protein is generated synthetically. This means a vast range of chemical modifications, including non-canonical amino acids (ncAA), backbone modifications, chemical handles, fluorescent or spectroscopic labels and any combination of these can be incorporated.

Febrile temperature change modulates CD4 T cell differentiation via a TRPV channel-regulated Notch-dependent pathway.

Fever is a conserved and prominent response to infection. Yet, the issue of how CD4 T cell responses are modulated if they occur at fever temperatures remains poorly addressed. We have examined the priming of naive CD4 T cells in vitro at fever temperatures, and we report notable fever-mediated modulation of their cytokine commitment.

Copper(i) catalyzed synthesis of selanyl methylene 4-chromanol and aurone derivatives.

An efficient copper-catalyzed cyclization cascade approach towards highly functionalized methylene 4-chromanol and aurone derivatives has been developed from reactions of ynols via 6-exo-dig and 5-exo-dig cyclization respectively. The catalysis involves alkyne activation via diorgano-diselenides and also their regioselective incorporation into the methylene 4-chromanol and aurone derivative core and is an open-air transformation.

Copper(I)-Catalyzed Synthesis of Functionalized Indolizinones from Substituted Pyridine Homologated Ynones.

An efficient two-component copper-catalyzed cyclization cascade approach toward highly functionalized indolizinone heterocycles has been developed from reactions of pyridine-, isoquinoline-, and quinoline ynones, via 5-- cyclization. The catalysis involves the activation by diorgano diselenide and diorgano disulfide and also their incorporation into the indolizinone core. In addition, the obtained substituted indolizinones were readily transformed into 1-(organochalcogenyl)indolizin-2-ols, which are important building blocks in organic synthesis.

Ruthenium(VIII)-Catalyzed ipso-Dearomative Spiro-Etherification and Spiro-Amidation of Phenols.

An open air ruthenium(VIII)-catalyzed oxidative spiro-etherification as well as spiro-amidation of phenols has been performed. The transformation works satisfactorily with both phenols and naphthols and thus exhibits a wide range of flexibility. The catalysis is performed in open air at room temperature with a yield of ≤95%.

A Dual-App Nucleoside Probe Provides Structural Insights into the Human Telomeric Overhang in Live Cells.

Understanding the topology adopted by individual G-quadruplex (GQ)-forming sequences in vivo and targeting a specific GQ motif among others in the genome will have a profound impact on GQ-directed therapeutic strategies. However, this remains a major challenge as most of the tools poorly distinguish different GQ conformations and are not suitable for both cell-free and in-cell analysis. Here, we describe an innovative probe design to investigate GQ conformations and recognition in both cell-free and native cellular environments by using a conformation-sensitive dual-app nucleoside analogue probe.

Protein-Lipid Interfaces Can Drive the Functions of Membrane-Embedded Protein-Protein Complexes.

The roles of surrounding membrane lipids in the functions of transmembrane and peripheral membrane proteins are largely unknown. Herein, we utilize the recently reported structures of the TRPV1 ion channel protein bound to its potent protein agonist, the double-knot toxin (DkTx), as a model system to investigate the roles of toxin-lipid interfaces in TRPV1 activation by characterizing a series of DkTx variants electrophysiologically. Together with membrane partitioning experiments, these studies reveal that toxin-lipid interfaces play an overwhelmingly dominant role in channel activation as compared to lipid-devoid toxin-channel interfaces.

Rhodium-Catalyzed Insertion Reaction of PhP Group of Pentaphenylcyclopentaphosphine with Acyclic and Cyclic Disulfides.

Organophosphorus compounds with a phosphorus atom attached to a phenyl group and two organothio/organoseleno groups were synthesized using the rhodium-catalyzed insertion reaction of the PhP group of pentaphenylcyclopentaphosphine (PhP) with acyclic disulfides and diselenides. The method was applied to the synthesis of heterocyclic compounds containing the S-P-S group by the reaction of (PhP) and cyclic disulfides such as 1,2-dithietes, 1,2-dithiocane, 1,4,5-dithiopane, and 1,2-dithiolanes.

Atom-Economical Palladium Carbon-Catalyzed de Novo Synthesis of Trisubstituted Nicotinonitriles.

A de novo palladium carbon-catalyzed synthesis of trisubstituted nicotinonitriles from easily synthesized homopropagylic or homoallylic aromatic alcohols in the presence of nitriles has been explored. The mechanism proceeds with an interesting generation of a Pd(II)-C palladacycle followed by an oxidative aromatization to generate the pyridine core. The pyridine core is generated with a noteworthy C-C bond cleavage in the case of the substituted nitriles.

Phenyl trimethyl ammonium tribromide mediated robust one-pot synthesis of spiro-oxacycles - an economic route - stereoselective synthesis of oxaspirohexacyclodieneones.

This paper entails the first recognition of Phenyl Trimethyl Ammonium Tribromide (PTAB) as an effective reagent for spiro-cyclizations proceeding via oxidative dearomatization. The experiment exhibits economical, metal and ligand free one-pot accomplishment of these significant transformations. The described protocol presents the first generalised methodology of spiro-oxacycle synthesis which can be applied towards various directions.