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Gram-negative bacteria are intrinsically resistant to a plethora of antibiotics that effectively inhibit the growth of Gram-positive bacteria. The intrinsic resistance of Gram-negative bacteria to classes of antibiotics, including rifamycins, aminocoumarins, macrolides, glycopeptides, and oxazolidinones, has largely been attributed to their lack of accumulation within cells due to poor permeability across the outer membrane, susceptibility to efflux pumps, or a combination of these factors. Due to the difficulty in discovering antibiotics that can bypass these barriers, finding targets and compounds that increase the activity of these ineffective antibiotics against Gram-negative bacteria has the potential to expand the antibiotic spectrum. In this study, we investigated the genetic determinants for resistance to rifampicin, novobiocin, erythromycin, vancomycin, and linezolid to determine potential targets of antibiotic-potentiating compounds. We subsequently performed a high-throughput screen of ∼50,000 diverse, synthetic compounds to uncover molecules that potentiate the activity of at least one of the five Gram-positive-targeting antibiotics. This led to the discovery of two membrane active compounds capable of potentiating linezolid and an inhibitor of lipid A biosynthesis capable of potentiating rifampicin and vancomycin. Furthermore, we characterized the ability of known inhibitors of lipid A biosynthesis to potentiate the activity of rifampicin against Gram-negative pathogens.

Vinyl sulfides accessed via Wittig olefination with thioalkylphosphonium salts are used as aldehyde- or ketone surrogates in Fischer indole reactions. These vinyl sulfides react with arylhydrazines in the presence of TsOH·H2O in refluxing ethanol or dichloroethane to yield diverse 3-substituted and 2,3-disubstituted indoles or azaindoles. The utility of this chemistry is highlighted with the efficient preparation of three biomedically relevant compounds: 4-aza-melatonin, a furoindoline, and an indomethacin-like CRTh2 antagonist.

Phosphines were previously unusable as Pummerer-type nucleophiles due to competing redox chemistry with sulfoxides. Here we circumvent this problem to achieve a formal phosphine Pummerer reaction that offers thioalkyl phosphonium salts that, in turn, give rise to diverse vinyl sulfides via Wittig olefinations. Thirty vinyl sulfides are thus prepared from (alkylthioalkyl)triphenyl phosphonium salts and aldehydes. The hydrolysis of these vinyl sulfides offers an efficient and versatile two-step one-carbon homologation of aldehydes to ketones.

Sulfamates and sulfamides are most often synthesized from alcohols and amines with sulfamoyl chloride, which is an unstable reagent. We have identified hexafluoroisopropyl sulfamate (HFIPS) as a bench-stable solid that reacts readily with a wide variety of alcohols, amines, phenols, and anilines under mild reaction conditions. The sole byproduct of the reaction is hexafluoroisopropanol (HFIP) and reaction products can often be isolated in high purity after an aqueous workup (optional) and removal of solvents by evaporation.

The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.

The exchange protein activated by cAMP (EPAC) is a promising drug target for a wide disease range, from neurodegeneration and infections to cancer and cardiovascular conditions. A novel partial agonist of the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its mechanism of action remains poorly understood. Here, we utilize NMR spectroscopy to map the I942-EPAC1 interactions at atomic resolution and propose a mechanism for I942 partial agonism. We found that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP). These results not only reveal the molecular basis for the I942 vs cAMP mimicry and competition, but also suggest that the partial agonism of I942 arises from its ability to stabilize an inhibition-incompetent activation intermediate distinct from both active and inactive EPAC1 states. The mechanism of action of I942 may facilitate drug design for EPAC-related diseases.

Exchange proteins directly activated by cAMP (EPAC) are guanine nucleotide exchange factors for the small GTPases, Rap1 and Rap2. They regulate several physiological functions and mitigation of their activity has been suggested as a possible treatment for multiple diseases such as cardiomyopathy, diabetes, chronic pain, and cancer. Several EPAC-specific modulators have been developed, however studies that quantify their structure-activity relationships are still lacking. Here we propose a quantitative structure-activity relationship (QSAR) model for a series of EPAC-specific compounds. The model demonstrated high reproducibility and predictivity and the predictive ability of the model was tested against a series of compounds that were unknown to the model. The compound with the highest predicted affinity was validated experimentally through fluorescence-based competition assays and NMR experiments revealed its mode of binding and mechanism of action as a partial agonist. The proposed QSAR model can, therefore, serve as an effective screening tool to identify promising EPAC-selective drug leads with enhanced potency.

INTRO: Patients with brain metastases (BM) face a 90% mortality rate within one year of their diagnosis and they lack targeted therapeutic options, particularly preventative or interceptional ones. METHODS: The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from patient-derived BM from primary lung and breast cancers and melanoma. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective metastatic cascades and allowed characterization of a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but present a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RESULTS: Targeting premetastatic BM cells is a feasible interceptional strategy to block BM, but druggable targets are still very limited. Here, we applied RNA sequencing of premetastatic BM cells to reveal a unique deregulated transcriptomic profile that is specific to premetastatic cells regardless of primary tumor origin. Subsequent Connectivity Map analysis revealed compounds that we biologically characterized in vitro for selective anti-BMIC phenotypes. This effort led us to identify a tool compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Follow up preclinical studies showed that treatment with this tool compound reduces the tumor burden of mice compared to placebo, while providing a significant survival advantage. Mass spectrometry-based metabolomics and CRISPR knock-out studies directly validated our tool compound’s target, Target X, as a targetable therapeutic vulnerability in BM, where pharmacological and genetic perturbation of Target X attenuates BM cell proliferation both in vitro and in vivo. We have now begun a large-scale medicinal chemistry campaign to develop a novel, brain penetrant Target X-inhibitor with a drug-like pre-clinical profile validated by our in vivo experimental models. This advanced drug candidate will be ready for later stage preclinical development and subsequent clinical development. CONCLUSION: This potential first-in-class anti-metastatic therapy may provide an alternative interceptional treatment strategy for patients experiencing BM that are otherwise limited to palliation. Our work provides a new model for target discovery and validation to develop more effective preventative therapeutic strategies for patients with metastatic disease. Citation Format: Agata M. Kieliszek, Daniel Mobilio, Blessing I. Bassey-Archibong, Jarrod Johnson, Nikoo Aghaei, William Gwynne, Dillon McKenna, Minomi K. Subapanditha, Chitra Venugopal, Jakob Magolan, Sheila K. Singh. Uncovering a new therapeutic vulnerability for preventing brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2474.

The current standard of care for (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.

[Image: see text] Metergoline is a semisynthetic ergot alkaloid identified recently as an inhibitor of the Gram-negative intracellular pathogen Salmonella Typhimurium (S. Tm). With the previously unknown antibacterial activity of metergoline, we explored structure–activity relationships (SARs) with a series of carbamate, urea, sulfonamide, amine, and amide analogues. Cinnamide and arylacrylamide derivatives show improved potency relative to metergoline against Gram-positive bacteria, and pyridine derivative 38 is also effective against methicillin-resistant Staphylococcus aureus (MRSA) in a murine skin infection model. Arylacrylamide analogues of metergoline show modest activity against wild-type (WT) Gram-negative bacteria but are more active against strains of efflux-deficient S. Tm and hyperpermeable Escherichia coli. The potencies against WT strains of E. coli, Acinetobacter baumannii, and Burkholderia cenocepacia are also improved considerably (up to >128-fold) with the outer-membrane permeabilizer SPR741, suggesting that the ergot scaffold represents a new lead for the development of new antibiotics.

Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to subinhibitory concentrations of antibiotics increases the formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits the growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce interleukin-1β (IL-1β) production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross-resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues synergize with penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants.

This study focuses on the biosynthesis of a suite of specialized metabolites from Cannabis that are known as the 'bibenzyls'. In planta, bibenzyls accumulate in response to fungal infection and various other biotic stressors; however, it is their widely recognized anti-inflammatory properties in various animal cell models that have garnered recent therapeutic interest. We propose that these compounds are synthesized via a branch point from the core phenylpropanoid pathway in Cannabis, in a three-step sequence. First, various hydroxycinnamic acids are esterified to acyl-coenzyme A (CoA) by a member of the 4-coumarate-CoA ligase family (Cs4CL4). Next, these CoA esters are reduced by two double-bond reductases (CsDBR2 and CsDBR3) that form their corresponding dihydro-CoA derivatives from preferred substrates. Finally, the bibenzyl backbone is completed by a polyketide synthase that specifically condenses malonyl-CoA with these dihydro-hydroxycinnamoyl-CoA derivatives to form two bibenzyl scaffolds: dihydropiceatannol and dihydroresveratrol. Structural determination of this 'bibenzyl synthase' enzyme (CsBBS2) indicates that a narrowing of the hydrophobic pocket surrounding the active site evolved to sterically favor the non-canonical and more flexible dihydro-hydroxycinnamoyl-CoA substrates in comparison with their oxidized relatives. Accordingly, three point mutations that were introduced into CsBBS2 proved sufficient to restore some enzymatic activity with an oxidized substrate, in vitro. Together, the identification of this set of Cannabis enzymes provides a valuable contribution to the growing 'parts prospecting' inventory that supports the rational metabolic engineering of natural product therapeutics.

The natural product veranamine was isolated from the marine sponge Verongula rigida. It contains a unique heterocyclic scaffold and demonstrates in vivo antidepressant activity and selective affinity for 5HT2B and sigma-1 receptors. The first total synthesis of veranamine is reported. Our scalable synthesis offers veranamine in six steps and 25% yield via an unprecedented vinylogous Pictet-Gams pyridine formation strategy. Veranamine is a promising new lead compound for antidepressant drug development.

The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate pre-formed biofilms and stationary phase cells persistent to antibiotics. We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.

Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to sub-inhibitory concentrations of antibiotics increases formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce IL-1β production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues potentiate the activity of penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants.

The outer membrane of Gram-negative bacteria is a formidable permeability barrier which allows only a small subset of chemical matter to penetrate. This outer membrane barrier can hinder the study of cellular processes and compound mechanism of action, as many compounds including antibiotics are precluded from entry despite having intracellular targets. Consequently, outer membrane permeabilizing compounds are invaluable tools in such studies. Many existing compounds known to perturb the outer membrane also impact inner membrane integrity, such as polymyxins and their derivatives, making these probes nonspecific. We performed a screen of ∼140 000 diverse synthetic compounds, for those that antagonized the growth inhibitory activity of vancomycin at 15 °C in Escherichia coli, to enrich for chemicals capable of perturbing the outer membrane. This led to the discovery that liproxstatin-1, an inhibitor of ferroptosis in human cells, and MAC-0568743, a novel cationic amphiphile, could potentiate the activity of large-scaffold antibiotics with low permeation into Gram-negative bacteria at 37 °C. Liproxstatin-1 and MAC-0568743 were found to physically disrupt the integrity of the outer membrane through interactions with lipopolysaccharide in the outer leaflet of the outer membrane. We showed that these compounds selectively disrupt the outer membrane while minimally impacting inner membrane integrity, particularly at the concentrations needed to potentiate Gram-positive-targeting antibiotics. Further exploration of these molecules and their structural analogues is a promising avenue for the development of outer membrane specific probes.

The current standard of care (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “pre-metastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target pre-metastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR). Following the observation that CF reduced circulating PCSK9 levels and increased hepatic LDLR expression, additional CF-derived analogs with increased potency for PCSK9 inhibition compared to CF itself were developed. The PCSK9-lowering effect of CF was subsequently confirmed in a cohort of healthy volunteers. Mechanistically, we demonstrate that CF increases hepatic endoplasmic reticulum (ER) Ca

The natural product veranamine was isolated from the marine sponge

Summary Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

Summary Salmonella serovars are leading causes of gastrointestinal disease and have become increasingly resistant to fluoroquinolone and cephalosporin antibiotics. Overcoming this healthcare crisis requires new approaches in antibiotic discovery and the identification of unique bacterial targets. In this work, we describe a chemical genomics approach to identify inhibitors of Salmonella virulence. From a cell-based, promoter reporter screen of ∼50,000 small molecules, we identified dephostatin as a non-antibiotic compound that inhibits intracellular virulence factors and polymyxin resistance genes. Dephostatin disrupts signaling through both the SsrA-SsrB and PmrB-PmrA two-component regulatory systems and restores sensitivity to the last-resort antibiotic, colistin. Cell-based experiments and mouse models of infection demonstrate that dephostatin attenuates Salmonella virulence in vitro and in vivo, suggesting that perturbing regulatory networks is a promising strategy for the development of anti-infectives.

Antibiotics halt the growth of bacteria by targeting core, essential physiology that is required for life on standard microbiological media. Many more biochemical and virulence processes, however, are required for bacteria to cause infection in a host. Indeed, chemical inhibitors of the latter processes are overlooked using conventional antibiotic drug discovery approaches. Here, we use human blood serum as an alternative growth medium to explore new targets and compounds. High-throughput screening of genetic and chemical libraries identified compounds targeting biological activities required by Klebsiella pneumoniae to grow in serum, such as nucleobase biosynthesis and iron acquisition, and showed that serum can chemically transform compounds to reveal cryptic antibacterial activity. One of these compounds, ruthenium red, was effective in a rat bloodstream infection model. Our data demonstrate that human serum is an effective tool to find new chemical matter to address the current antibiotic resistance crisis.

Antibiotics halt the growth of bacteria in the laboratory by targeting core, essential physiology that is required for life on standard microbiological media. Many more biochemical and virulence processes, however, are required for bacteria to cause infection in a host. Indeed, chemical inhibitors of the latter processes are overlooked using conventional antibiotic drug discovery approaches. Here, we use human blood serum as an alternative growth medium to explore new targets and compounds. High-throughput screening of genetic and chemical libraries identified compounds targeting biological activities required by Klebsiella pneumoniae to grow in serum, such as nucleobase biosynthesis and iron acquisition, and showed that serum can chemically transform compounds to reveal cryptic antibacterial activity. One of these compounds, ruthenium red, was effective in a rat bloodstream infection model. Our data demonstrate that human serum is an effective tool to find new chemical matter to address the current antibiotic resistance crisis.

A 1,2-regioselective reduction of α,β-unsaturated ketones to their corresponding allylic alcohols is accomplished with NaBH4 in the presence of acidic activated alumina rehydrated to the Brockmann II grade by adding 3 % w/w water. The substrate scope includes eight ketones reduced in high regio- and diastereoselectivity to their corresponding allylic alcohols. This is the first example of the strategy of systematically tuning the surface chemistry of alumina via partial rehydration in order to modulate selectivity in a reaction. Alumina is an appealing alternative to the common Luche reduction additive, CeCl3, from the perspective of cost and procedural simplicity.

A procedure for the synthesis of biaryl ketones by a palladium-catalyzed Suzuki–Miyaura cross-coupling reaction between phenyltrifluoroborates and benzoyl chlorides is described. Organotrifluoroborates are unique to other cross-coupling reagents as they have a high functional-group tolerance and are moisture-stable. Moderate to excellent yields were obtained for all substrates tested.

Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella., Salmonella Typhimurium replicates within host phagocytes. Here, the authors show that a known psychoactive drug (metergoline) inhibits growth of the pathogen in macrophages, disrupts the proton motive force at the bacterial cytoplasmic membrane, and extends animal survival during systemic infection.

Dimethyl sulfoxide is generally characterized as a solvent and oxidant rather than as a substrate, building block, or synthon in organic chemistry. However, an abundance of reports have recently appeared that demonstrate dimethyl sulfoxide acting in these roles. This review article offers a comprehensive summary of the literature on this topic until the end of 2015. Synthetic transformations that have utilized the ‘C–S–C’, ‘C’, and ‘C–S’ fragments of dimethyl sulfoxide as building blocks are systematically summarized. 1 Introduction 2 History and Recent Highlights of DMSO-Based Oxidations 3 DMSO-Based Methylthiomethylation (–CH2SMe) 4 DMSO as a One-Carbon Synthon 4.1 DMSO-Based Methylation (–Me) 4.2 DMSO-Based Methylenation (–CH2–) 4.3 DMSO-Based Annulation/Aromatization (=CH–) 4.4 DMSO-Based Formylation (–CHO) 4.5 DMSO-Based Cyanation (–CN) 5 DMSO as Synthon for ‘S–C’ Functionalities 5.1 DMSO-Based Thiomethylation (–SMe) 5.2 DMSO-Based Methylsulfonylation (–SO2Me) 6 Summary and Conclusions

A simple and inexpensive methodology is reported for the conversion of alkenes to 1,2-dibromo alkanes via oxidative bromination using HBr paired with dimethyl sulfoxide, which serves as the oxidant as well as cosolvent. The substrate scope includes 21 olefins brominated in good to excellent yields. Three of six styrene derivatives yielded bromohydrins under the reaction conditions.

A unique synthesis of aryl methyl sulfides is reported proceeding via reduction of dimethylsulfoxide to dimethylsulfide at elevated temperature in the presence of Hunig’s base followed by nucleophilic aromatic substitution and demethylation. Activated aryl fluorides, chlorides, and nitrobenzenes are suitable substrates with 13 examples provided. Dimethylsulfoxide serves as a simple and inexpensive formal source of the thiomethyl moiety.

Preparation of mixed carbonates proceeded in one step from ketones and aldehydes via treatment with NaBH4 in dimethyl or diethyl carbonate solvent at elevated temperatures. This is an efficient and convenient alternative to the traditional two-step sequence of carbonyl reduction to alcohol and subsequent carbonate formation by treatment with an alkyl chloroformate. 25 examples are presented from 49 to 92% yield, highlighting the versatility of this reaction.

Vanadium pentoxide is evaluated as a dehydroaromatization reagent. Tetrahydrocarbazole is readily aromatized by V2O5 in refluxing acetic acid under both stoichiometric and catalytic conditions. Indoline, tetrahydroquinoline, and tetrahydroquinoxaline are effectively aromatized by V2O5/silica in refluxing toluene.

A procedure for the synthesis of biaryl ketones by a palladium-catalyzed Suzuki–Miyaura cross-coupling reaction between phenyltrifluoroborates and benzoyl chlorides is described. Organotrifluoroborates are unique to other cross-coupling reagents as they have a high functional-group tolerance and are moisture-stable. Moderate to excellent yields were obtained for all substrates tested.

A 1,2-regioselective reduction of α,β-unsaturated ketones to their corresponding allylic alcohols is accomplished with NaBH4 in the presence of acidic activated alumina rehydrated to the Brockmann II grade by adding 3 % w/w water. The substrate scope includes eight ketones reduced in high regio- and diastereoselectivity to their corresponding allylic alcohols. This is the first example of the strategy of systematically tuning the surface chemistry of alumina via partial rehydration in order to modulate selectivity in a reaction. Alumina is an appealing alternative to the common Luche reduction additive, CeCl3, from the perspective of cost and procedural simplicity.

Dimethyl sulfoxide is generally characterized as a solvent and oxidant rather than as a substrate, building block, or synthon in organic chemistry. However, an abundance of reports have recently appeared that demonstrate dimethyl sulfoxide acting in these roles. This review article offers a comprehensive summary of the literature on this topic until the end of 2015. Synthetic transformations that have utilized the ‘C–S–C’, ‘C’, and ‘C–S’ fragments of dimethyl sulfoxide as building blocks are systematically summarized. 1 Introduction 2 History and Recent Highlights of DMSO-Based Oxidations 3 DMSO-Based Methylthiomethylation (–CH2SMe) 4 DMSO as a One-Carbon Synthon 4.1 DMSO-Based Methylation (–Me) 4.2 DMSO-Based Methylenation (–CH2–) 4.3 DMSO-Based Annulation/Aromatization (=CH–) 4.4 DMSO-Based Formylation (–CHO) 4.5 DMSO-Based Cyanation (–CN) 5 DMSO as Synthon for ‘S–C’ Functionalities 5.1 DMSO-Based Thiomethylation (–SMe) 5.2 DMSO-Based Methylsulfonylation (–SO2Me) 6 Summary and Conclusions

The emerging "anti-austerity" anti-cancer therapeutic strategy targets the ability of certain cancer cell lines, particularly pancreatic cancer, to survive nutrient deprivation. While biochemical pathways for the tolerance to nutrient deprivation are still not well understood, a growing number of inhibitors of this process are being discovered. A number of natural products have been isolated, structurally characterized and evaluated as inhibitors of austerity, thereby providing valuable initial structure-activity relationship data.

A series of functionalized coumarins were synthesized and evaluated for their capacity to inhibit the resistance to starvation of pancreatic cancer cells. This form of cytotoxicity, termed 'antiausterity' activity, was evaluated using a preferential cytotoxicity assay that compared cell survival in nutrient poor and nutrient rich conditions. Six of the seventeen compounds showed weak antiausterity activity against PANC-1. Compound 34 was active against PANC-1, MIA PaCa-2, and Capan-1 cancer cell lines. All of the compounds tested were simplified structural analogs of previously reported natural product leads. Six of the compounds, including 34, contain functionalized triazoles as novel potential bioisosteres of the side chain of the natural product angelmarin. Overall, the analogs were found to have low antiausterity activity relative to the corresponding natural products.

The reaction works well with terminal as well as internal olefins giving the respective dibromo adducts in good to excellent yields.

Pyrroles, indoles, and surprisingly, indolines, when equipped with a pendant malonyl group on the nitrogen atom, were effective substrates in a Mn(III)-mediated oxidative cyclization reaction, yielding the 1,2-annulated products in good to excellent yields. When indole acetonitrile was used as a substrate this method provided a rapid synthesis of a tetracyclic tronocarpine subunit.

[reaction: see text] The synthesis of the highly substituted indole portion of the complex tremorgenic natural products lolicine A and B is presented. The Diels-Alder reaction of a quinone monoimine enables the synthesis of an appropriately substituted indole. The key step in the synthesis is a tandem isopropenyl cuprate addition/aldol cyclocondensation which provides the necessary functionality for elaboration to the 2,2,5,5-tetramethyltetrahydrofuran.

4-Bromonitrobenzene as well as 1,3-dinitrobenzene are unreactive, and 2-fluoropyridine decomposes under the reaction conditions.

Various N-heterocyclic compounds are readily aromatized using V2O5 as dehydroaromatization reagent.

A series of nineteen benzimidazoles are prepared from ortho-nitroanilines via one-pot transfer hydrogenation, condensation, and dehydrogenation enabled by the concurrent use of two heterogeneous catalysts: montmorillonite-K10 and Pd/C. This strategy is further employed to accomplish a five-step, three-component synthesis of an antifungal benzimidazoquinazoline using a simple one-pot procedure.

A series of nineteen benzimidazoles are prepared from ortho-nitroanilines via one-pot transfer hydrogenation, condensation, and dehydrogenation enabled by the concurrent use of two heterogeneous catalysts: montmorillonite-K10 and Pd/C. This strategy is further employed to accomplish a five-step, three-component synthesis of an antifungal benzimidazoquinazoline using a simple one-pot procedure.