Evaluation of the Mammalian Aquaporin Inhibitors Auphen and Z433927330 in Treating Breast Cancer.

AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment.

Pseudoaromaticity-driven, transition metal detection by squaraine-derived enol phosphonium ylide chemodosimeters.

The addition of PBu to -substituted dianiline squaraine dyes leads to bench stable ylides. Exposure to a metal analyte in solution, results in P abstraction and rapid disruption of the ylide conjugation to promote reversion back to the squaraine dye giving an immediate turn-on colorimetric response. The stoichiometric sensitivity and accessibility of these chemodosimeters constitute effective organic dyes for trace transition metal detection.

A Proline-Squaraine Ligand Framework (Pro-SqEB) for Stereoselective Rhodium(II)-Catalyzed Cyclopropanations.

A proline-squaraine ligand (Pro-SqEB) that demonstrates high levels of stereoselectivity in olefin cyclopropanations when anchored to a Rh scaffold is introduced. High yields and enantioselectivities were achieved in the cyclopropanation of alkenes with diazo compounds in the presence of Rh(Pro-SqEB). Notably, the unique electronic and steric design of this catalyst enabled the use of polar solvents that are otherwise incompatible with most Rh complexes.

Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer.

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 () as the driver oncogene for the amplicon at 1q21.

Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection.

Group A (GAS, ) is a Gram-positive human pathogen that employs several secreted and surface-bound virulence factors to manipulate its environment, allowing it to cause a variety of disease outcomes. One such virulence factor is Streptolysin S (SLS), a ribosomally-produced peptide toxin that undergoes extensive post-translational modifications. The activity of SLS has been studied for over 100 years owing to its rapid and potent ability to lyse red blood cells, and the toxin has been shown to play a major role in GAS virulence .

Syntheses of Symmetrical and Unsymmetrical Lysobisphosphatidic Acid Derivatives.

Recent years have witnessed significant achievements in the field of organic chemistry, which have led to new drugs and the discovery of new and biologically interesting molecules. Herein, we describe a practical and efficient approach to the synthesis of enantiomerically pure and diverse lysobisphosphatidic acid analogues. The key feature of the synthesis is a one-pot, sequential phosphorylation of a protected -2--oleoyl glycerol or -3--oleoyl glycerol with 2-cyanoethyl ,-diisopropylchlorophosphoramidite, followed by oxidation.

Generation of Functionalized Azepinone Derivatives via a (4 + 3)-Cycloaddition of Vinyl Ketenes and α-Imino Carbenes Derived from -Sulfonyl-triazoles.

An intermolecular Rh-catalyzed, formal (4 + 3)-cycloaddition between vinyl ketenes and -sulfonyl-1,2,3-triazoles for the construction of azepinone products is described. Employing vinyl ketenes as a 1,4-dipolar surrogate, instead of the more commonly used dienyl moieties, allows for the intermolecular and selective formation of azepinone products over a potential (3 + 2)-cycloadduct under mild reaction conditions allows for the generation of azepinone products in up to 98% yield.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition.

Oxyphosphonium Enolate Equilibria in a (4+1)-Cycloaddition Approach toward Quaternary C3-Spirooxindole Assembly.

An efficient and convergent (4+1)-cycloaddition strategy toward the construction of spirooxindole benzofurans that involves the intermediacy of an isatin-derived oxyphosphonium enolate is presented. Mechanistic investigations employing in situ NMR analysis of the reaction mixture revealed a correlation between phosphonium enolate structure and product distribution that was heavily influenced by the solvent and reaction temperature.

A Phosphine-Mediated Dearomative Skeletal Rearrangement of Dianiline Squaraine Dyes.

A phosphorus(III)-mediated dearomatization of -substituted dianiline squaraine dyes results in an unusual skeletal rearrangement to provide exotic, highly conjugated benzofuranone and oxindole scaffolds bearing a C3 side chain comprised of a linear conflagration of an enol, a phosphorus ylide, and 2,4-disubstituted aniline. Employing experimental and computational analysis, a mechanistic evaluation revealed a striking dependence on the acidity of the aniline substituent. Notably, the rearrangement adducts underwent rapid and complete reversion to the parent squaraine in the presence of a Brønsted acid.

Ionic liquid enables highly efficient low temperature desalination by directional solvent extraction.

Seawater desalination plays a critical role in addressing the global water shortage challenge. Directional Solvent Extraction (DSE) is an emerging non-membrane desalination technology that features the ability to utilize very low temperature waste heat (as low as 40 °C). This is enabled by the subtly balanced solubility properties of directional solvents, which do not dissolve in water but can dissolve water and reject salt ions.

Diverting β-Hydride Elimination of a π-Allyl Pd Carbene Complex for the Assembly of Disubstituted Indolines via a Highly Diastereoselective (4 + 1)-Cycloaddition.

A Pd-catalyzed formal (4 + 1)-cycloaddition approach to 2,3-disubstituted dihydroindoles is described. The diastereoselective formation of dihydroindoles that is highlighted by a carbene migratory insertion/reductive elimination sequence proceeding via a π-allyl Pd-species compliments existing methods of indoline assembly.

Combined Scaffold Evaluation and Systems-Level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes.

With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold-directed synthesis with a hybrid experimental and transcriptome analysis to identify bis-spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first-in-class cancer therapeutic candidates.

Nucleophilic addition of phosphorus(iii) derivatives to squaraines: colorimetric detection of transition metal-mediated or thermal reversion.

Nucleophilic addition of phosphorus(iii) agents to the electrophilic core of intensely colored squaraine dyes gives a bleached zwitterionic adduct in good to excellent yields (up to 99%) at room temperature. The process can be reversed by adding specific transition metal complexes with high phosphorous(iii) affinity.

An unusual stereoretentive 1,3-quaternary carbon shift resulting in an enantioselective Rh-catalyzed formal [4+1]-cycloaddition between diazo compounds and vinyl ketenes.

Enantioselective quaternary carbon construction in the assembly of cyclopentenones employing a Rh-catalyzed, formal [4+1]-cycloaddition is described. A Rh(-TCPTTL)-catalyzed cyclopropanation of a vinyl ketene with a disubstituted diazo compound initiates a stereoretentive, accelerated ring expansion to provide the cycloadduct in good to excellent yields and enantioselectivity.

Aroyl Isocyanates as 1,4-Dipoles in a Formal [4 + 1]-Cycloaddition Approach toward Oxazolone Construction.

A formal phosphine-mediated [4 + 1]-cycloaddition between a 1,2-dicarbonyl and an aroyl isocyanate to provide oxazolones bearing a disubstituted C5 center is described. By exploiting the carbene-like reactivity of oxyphosphonium enolates as C1 synthons and aroyl isocyanates as formal 1,4-dipoles, oxazolones and spiroooxindole oxazolones are constructed in high yields (39-99%).

A Rhodium(II)-Catalyzed Formal [4+1]-Cycloaddition toward Spirooxindole Pyrrolone Construction Employing Vinyl Isocyanates as 1,4-Dipoles.

A Rh -catalyzed, formal [4+1]-cycloaddition between diazooxindoles as electrophilic C synthons and 1,3-heterodienes for the construction of spirooxindole pyrrolones is described. Employing vinyl isocyanates as 1,4-dipoles, the cycloannulation occurs under relatively mild conditions and provides the corresponding pyrrolones in good to excellent yields.

Rearrangement of an Intermediate Cyclopropyl Ketene in a Rh-Catalyzed Formal [4 + 1]-Cycloaddition Employing Vinyl Ketenes as 1,4-Dipoles and Donor-Acceptor Metallocarbenes.

A Rh-catalyzed formal [4 + 1]-cycloaddition approach toward spirooxindole cyclopentenones is described. The diastereoselective cyclopropanation of vinyl ketenes with diazooxindoles as C1 synthons initiated a relatively mild formal [1,3]-migration of an intermediate cyclopropyl ketene to provide spirooxindoles in good to excellent yields (36-99%).

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.

The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway.

Phosphorus(III)-Mediated Stereoconvergent Formal [4+1]-Cycloannulation of 1,2-Dicarbonyls and o-Quinone Methides: A Multicomponent Assembly of 2,3-Dihydrobenzofurans.

A phosphorus(III)-mediated formal [4+1]-cycloaddition of 1,2-dicarbonyls and o-quinone methides to provide 2,3-dihydrobenzofurans is described. By exploiting the carbene-like nature of dioxyphospholenes, dihydrobenzofurans bearing a quaternary center at C2 are obtained in 30-92% yield with diastereoselectivities up to ≥20:1. This study highlights the subtle steric interactions involved in the [4+1]-cycloannulation and the impact they have on yield and stereoselectivity in dihydrobenzofuran formation.

Activation of band 3 mediates group A Streptococcus streptolysin S-based beta-haemolysis.

Streptococcus pyogenes, or group A Streptococcus (GAS), is a human bacterial pathogen that can manifest as a range of diseases from pharyngitis and impetigo to severe outcomes such as necrotizing fasciitis and toxic shock syndrome. GAS disease remains a global health burden with cases estimated at over 700 million annually and over half a million deaths due to severe infections(1). For over 100 years, a clinical hallmark of diagnosis has been the appearance of complete (beta) haemolysis when grown in the presence of blood.

Redox and Lewis acid relay catalysis: a titanocene/zinc catalytic platform in the development of multicomponent coupling reactions.

A titanocene-catalyzed multicomponent coupling is described herein. Using catalytic titanocene, phosphine, and zinc dust, zinc acetylides can be generated from the corresponding iodoalkynes to affect sequential nucleophilic additions to aromatic aldehydes. The intermediate propargylic alkoxides are trapped in situ with acetic anhydride, which are susceptible to a second nucleophilic displacement upon treatment with a variety of electron-rich species, including acetylides, allyl silanes, electron-rich aromatics, silyl enol ethers, and silyl ketene acetals.

An umpolung approach toward N-aryl nitrone construction: a phosphine-mediated addition of 1,2-dicarbonyls to nitroso electrophiles.

An umpolung approach toward nitrone construction utilizing a phosphine-mediated addition of 1,2-dicarbonyls to nitroso compounds is reported. The reaction exhibits a high degree of chemoselectivity and provides direct access to isoxazolidines, imines, and trisubstituted alkenes.