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Simple Summary: Aquaporins (AQPs) have emerged as potential predictors of response to cancer therapy and as targets for increasing sensitivity to treatment. However, systemic therapeutic inhibition using pan-AQP or AQP-specific inhibitors has not been characterized for efficacy in treating breast cancer or as a component of combination treatment. We evaluated AQP inhibition using established AQP inhibitors in cytotoxicity and pharmacologic assays. This study identified AQPs as a targetable vulnerability in breast cancer. AQP inhibitors can increase therapeutic efficacy, both as single agents and in a combination therapy strategy, in treating breast cancer progression and metastasis. These results provide significant insights that support the future development of improved AQP inhibitors. 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. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. [ABSTRACT FROM AUTHOR]

The addition of PnBu3 to o-substituted dianiline squaraine dyes leads to bench stable ylides. Exposure to a metal analyte in solution, results in PIII 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. [ABSTRACT FROM AUTHOR]

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 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer. Breaking down the barrier to prostate cancer immunotherapy: Prostate cancer is minimally responsive to most immunotherapy approaches due to poor tumor infiltration of lymphocytes. Using mouse models of prostate cancer, Zhu et al. found that cancer cell expression of the chromatin effector Pygo2 promotes immunotherapy resistance by restraining tumor T cell infiltration and cytotoxicity. Pygo2's suppressive effects were mediated by promoting expression of the receptor tyrosine kinase Kit and activity of indoleamine 2,3-dioxygenase 1, which occurred independently of Wnt/β-catenin signaling. Genetic deletion or pharmacological inhibition of Pygo2 enhanced prostate tumor responses to a wide range of immunotherapies including adoptive T cell therapy, CXCR2 blockade, and PD-1/CTLA-4 immune checkpoint blockade. Together, these results demonstrate that Pygo2 regulates cancer cell-extrinsic immune features and represents a potential target for reducing prostate cancer resistance to immunotherapy. —CO [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS, Streptococcus pyogenes) 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 in vivo. We have previously demonstrated that SLS induces hemolysis by targeting the chloride-bicarbonate exchanger Band 3 in erythrocytes, indicating that SLS is capable of targeting host proteins to promote cell lysis. However, the possibility that SLS has additional protein targets in other cell types, such as keratinocytes, has not been explored. Here, we use bioinformatics analysis and chemical inhibition studies to demonstrate that SLS targets the electroneutral sodium-bicarbonate cotransporter NBCn1 in keratinocytes during GAS infection. SLS induces NF-kB activation and host cytotoxicity in human keratinocytes, and these processes can be mitigated by treating keratinocytes with the sodium-bicarbonate cotransport inhibitor S0859. Furthermore, treating keratinocytes with SLS disrupts the ability of host cells to regulate their intracellular pH, and this can be monitored in real time using the pH-sensitive dye pHrodo Red AM in live imaging studies. These results demonstrate that SLS is a multifunctional bacterial toxin that GAS uses in numerous context-dependent ways to promote host cell cytotoxicity and increase disease severity. Studies to elucidate additional host targets of SLS have the potential to impact the development of therapeutics for severe GAS infections. [ABSTRACT FROM AUTHOR]

(4+1)-Cyclizations are an underutilized disconnect for the formation of five-membered heterocyclic and carbocyclic frameworks. Herein we analyze methods employing oxyphosphonium enolates and RhII /PdII-metallocarbenes as C1 synthons in the presence of several four-atom components for the synthesis of 2,3-dihydrobenzofurans, 2,3-dihydroindoles, oxazolones, cyclopentenones, and pyrrolones. 1 Introduction 2 (4+1)-Cyclizations Employing Kukhtin–Ramirez-Like Reactivity 3 (4+1)-Cyclizations Employing a Cyclopropanation/Ring-Expansion Sequence 4 Pd-Catalyzed (4+1)-Cyclizations through Carbene Migratory Insertion/Reductive Elimination Processes 5 Summary [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. However, the low water yield of the state-of-the-art directional solvent (decanoic acid) significantly limits its throughput and energy efficiency. In this paper, we demonstrate that by using ionic liquid as a new directional solvent, saline water can be desalinated with much higher production rate and thus significantly lower the energy and exergy consumptions. The ionic liquid identified suitable for DSE is [emim][Tf2N], which has a much (~10×) higher water yield than the currently used decanoic acid. Using molecular dynamics simulations with Gibbs free energy calculations, we reveal that water dissolving in [emim][Tf2N] is energetically favorable, but it takes significant energy for [emim][Tf2N] ions to dissolve in water. Our findings may significantly advance the DSE technology as a solution to the challenges in the global water-energy nexus. Directional Solvent Extraction is an emerging non-membrane desalination technology for sea water desalination but is limited by throughput and energy efficiency. Here, the authors demonstrate that the production rate and energy efficiency can be increased by using ionic liquids as directional solvent. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A RhII-catalyzed, formal [4+1]-cycloaddition between diazooxindoles as electrophilic C1 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. [ABSTRACT FROM AUTHOR]

A RhII-catalyzed, formal [4+1]-cycloaddition between diazooxindoles as electrophilic C1 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. [ABSTRACT FROM AUTHOR]

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 chemo-selectivity and provides direct access to isoxazolidines, imines, and trisubstituted alkenes. [ABSTRACT FROM AUTHOR]

Hierarchically porous materials were developed using a two-step procedure by (1) the stacking of high-nitrogen-content polymer nanoparticles to produce inter-particle mesoporous space and (2) chemical activation to create intra-particle micropores. The materials exhibited efficient CO2 uptake and enhanced CO2/N2 selectivity, which is 40% higher than that of the control material without a hierarchical structure. [ABSTRACT FROM AUTHOR]

Atom hopping: A chlorophosphite‐mediated Beckmann ligation of oximes and p‐toluenesulfonyl azide gives access to N‐sulfonyl phosphoramidines in good to excellent yields. The reaction proceeds under exceptionally mild conditions and constitutes a bioorthogonal approach toward amidines by avoiding the use of amines and transition‐metal catalysts. dmp‐ol=3,3‐dimethylpropanediol. [ABSTRACT FROM AUTHOR]

Amin ‐ und metallfrei: Eine Chlorphosphit ‐ vermittelte Beckmann ‐ Ligation von Oximen mit p ‐ Toluolsulfonylazid liefert N ‐ Sulfonylphosphoramidine in guten bis exzellenten Ausbeuten. Die Reaktion läuft unter außergewöhnlich milden Bedingungen ab und bietet einen bioorthogonalen Ansatz für die Amidin ‐ Synthese unter Vermeidung von Aminen und Übergangsmetallkatalysatoren. dmp ‐ ol=3,3 ‐ Dimethylpropandiol. [ABSTRACT FROM AUTHOR]

Capture me! The first report of an N‐heterocyclic carbene (NHC) as a solid‐state carbon capture reagent is presented. Experimental and theoretical measurements demonstrate the ability of the NHC to react rapidly and stoichiometrically with CO2 at low partial pressures (see scheme). [ABSTRACT FROM AUTHOR]

Herein we describe a direct, multicomponent assembly of 1,5-enynes. The titanocene-catalyzed coupling of an aryl aldehyde, iodoalkyne, and allylsilane enables the convergent and rapid synthesis of this versatile architectural motif in good to excellent yields. [ABSTRACT FROM AUTHOR]

A chlorophosphite-modified, Staudinger-like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32-97 % yield after a simple aqueous workup without the need for a pre-activation step. The use of chlorophosphites as dual carboxylic acid-azide activating agents enables the formation of acyl CN bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described. [ABSTRACT FROM AUTHOR]

Herein, we report experimental and computational results for the carboxylation of abnormal anionic N-heterocyclic dicarbenes (NHDCs) with CO2. Under ambient dosing conditions, carbonyl addition occurs selectively at C4 without a second carboxylation event occurring at the C2 carbene center. [ABSTRACT FROM AUTHOR]

A (4+1)‐cycloaddition is reported between 1,2‐dicarbonyls and aza‐o‐quinone methide precursors to access 2,3‐dihydroindoles bearing a tetra‐substituted carbon center. The utilization of dioxyphospholenes as carbene surrogates provided dihydroindoles in 20–90 % yield, wherein the electronic nature of the dioxyphospholene impacts its role in the reaction. [ABSTRACT FROM AUTHOR]