A Dual Ni/Photoredox Cross-Coupling Approach toward Mandelic Acids.

Mandelic acid derivatives represent a valuable class of compounds due to their wide use in synthetic organic chemistry and the pharmaceutical sector. Herein, we report a novel reductive Ni/photoredox cross-coupling of readily accessible, bench stable N-alkoxyphthalimides and aryl halides to prepare unprotected mandelic acid ester derivatives. Mechanistic experiments suggest that this cross-coupling likely proceeds via a pathway that is distinct from previous reports using similar redox-active alkoxy radical precursors.

Synthesis of Borylated (Aminomethyl)cyclopropanes Using C1-Bisnucleophiles.

Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.

Photocatalytic O- to S-Rearrangement of Tertiary Cyclopropanols.

Despite the importance of heteroatom-substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman-Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O- to S-rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols-that are difficult to access by other methods-can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Long-term intermittent hypoxia in mice induces inflammatory pathways implicated in sleep apnea and steatohepatitis in humans.

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH), an independent risk factor for non-alcoholic fatty liver disease (NAFLD). While the molecular links between IH and NAFLD progression are unclear, immune cell-driven inflammation plays a crucial role in NAFLD pathogenesis. Using lean mice exposed to long-term IH and a cohort of lean OSA patients (n = 71), we conducted comprehensive hepatic transcriptomics, lipidomics, and targeted serum proteomics. Significantly, we demonstrated that long-term IH alone can induce NASH molecular signatures found in human steatohepatitis transcriptomic data. Biomarkers (PPARs, NRFs, arachidonic acid, IL16, IL20, IFNB, TNF-α) associated with early hepatic and systemic inflammation were identified. This molecular link between IH, sleep apnea, and steatohepatitis merits further exploration in clinical trials, advocating for integrating sleep apnea diagnosis in liver disease phenotyping. Our unique signatures offer potential diagnostic and treatment response markers, highlighting therapeutic targets in the comorbidity of NAFLD and OSA.

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

Nickel-Catalyzed Reductive Arylation of Redox Active Esters for the Synthesis of α-Aryl Nitriles: Investigation of a Chlorosilane Additive.

A nickel-catalyzed reductive cross-coupling of redox active N-hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in the pharmaceutical sciences. The reaction exhibits a broad scope, and many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents. Mechanistic studies reveal that reduction and decarboxylation of the NHP ester to the reactive radical intermediate are accomplished by a combination of a chlorosilane additive and Zn dust. We demonstrate that stoichiometric chlorosilane is essential for product formation and that chlorosilane plays a role beyond activation of the metal reductant.

Redox-Active Thiocarbonyl Auxiliaries in Ni-Catalyzed Cross-Couplings of Aliphatic Alcohols.

ConspectusThe Barton-McCombie deoxygenation reaction first established the use of O-alkyl thiocarbonyl derivatives as powerful redox-active agents for C(sp3)-O reduction. In recent years, first-row transition metals capable of engaging with alkyl radical intermediates generated from O-alkyl thiocarbonyl derivatives using alternative stoichiometric radical precursors have been developed. Given the ability of select Ni catalysts to both participate in single-electron oxidative addition pathways and intercept alkyl radical intermediates, our group has investigated the use of O-alkyl thiocarbonyl derivatives as electrophiles in novel cross-coupling reactions. After describing related work in this area, this Account will first summarize our entry point into this field. Here, we used the cyclopropane ring as a reporter of leaving group reactivity to aid in the design and optimization of a novel redox-active O-thiocarbamate leaving group for C(sp3)-O arylation. Motivation for this pursuit was driven by the propensity of the cyclopropane ring to undergo ring opening under polar (2e) oxidative addition pathways or to be maintained under single-electron (1e) conditions. Using these guiding principles, we developed a method for the deoxygenative arylation of cyclopropanol derivatives using a Ni catalyst without the need for a stoichiometric external reductant or photocatalyst. We next summarize our evaluation of an alternative redox-active O-thiocarbonyl imidazole auxiliary in a related deoxygenative cross-coupling. This work demonstrated an extension of our initial approach to the deoxygenative arylation of primary and secondary aliphatic alcohol derivatives. A brief mechanistic investigation revealed that this reaction likely proceeds via a distinct mechanism involving direct homolytic C(sp3)-O bond cleavage. We conclude this Account with a summary of work aimed toward a unique approach for thiocarboxylic acid derivative synthesis. This project was inspired by the efficiency of thionoester generation under most of the reaction conditions evaluated in our prior investigations. Using alcohol, amine, or thiol starting materials, which were activated with convenient thiocarbonyl sources in a single step, we optimized for a Ni-catalyzed cross-coupling capable of providing access to a range of thionoester, thioamide, or dithioester products. In summary, our work has revealed the potential of redox-active thiocarbonyl auxiliaries in Ni-catalyzed cross-couplings with C(sp3)-O electrophiles. We anticipate that the continued investigation of aliphatic thiocarbonyl derivatives as radical precursors with alternative single-electron inputs will be an area of continued growth in the years to come.

Nickel-Catalyzed Reductive Alkyne Hydrocyanation Enabled by Malononitrile and a Formaldehyde Additive.

The development of a nickel-catalyzed reductive alkyne hydrocyanation is described using 2-methyl-2-phenylmalononitrile (MPMN), a C-bound electrophilic transnitrilation reagent. Reproducibility issues led to the detection of oxidized hemiaminal impurities within N,N-dimethylacetamide. These impurities release formaldehyde in situ, which was ultimately identified as a critical reaction additive. A range of diaryl and aryl-alkyl alkynes underwent hydrocyanation. Mechanistic experiments revealed that formaldehyde and MPMN undergo a Ni-catalyzed reductive coupling of two π-components, leading to the controlled release of glycolonitrile as the active cyanating agent.

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cells dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cells ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulates lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation loose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo . Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.

The synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3' phosphate. We report that Nme2 knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells, NME2 mediates a gene transcriptional response to HFD leading to the repression of fatty acid accumulation and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling AcCoA usage between the competing paths of histone acetylation and fatty acid synthesis.

Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers.

BACKGROUND: In breast cancer, as in all cancers, genetic and epigenetic deregulations can result in out-of-context expressions of a set of normally silent tissue-specific genes. The activation of some of these genes in various cancers empowers tumours cells with new properties and drives enhanced proliferation and metastatic activity, leading to a poor survival prognosis. RESULTS: In this work, we undertook an unprecedented systematic and unbiased analysis of out-of-context activations of a specific set of tissue-specific genes from testis, placenta and embryonic stem cells, not expressed in normal breast tissue as a source of novel prognostic biomarkers. To this end, we combined a strict machine learning framework of transcriptomic data analysis, and successfully created a new robust tool, validated in several independent datasets, which is able to identify patients with a high risk of relapse. This unbiased approach allowed us to identify a panel of five biomarkers, DNMT3B, EXO1, MCM10, CENPF and CENPE, that are robustly and significantly associated with disease-free survival prognosis in breast cancer. Based on these findings, we created a new Gene Expression Classifier (GEC) that stratifies patients. Additionally, thanks to the identified GEC, we were able to paint the specific molecular portraits of the particularly aggressive tumours, which show characteristics of male germ cells, with a particular metabolic gene signature, associated with an enrichment in pro-metastatic and pro-proliferation gene expression. CONCLUSIONS: The GEC classifier is able to reliably identify patients with a high risk of relapse at early stages of the disease. We especially recommend to use the GEC tool for patients with the luminal-A molecular subtype of breast cancer, generally considered of a favourable disease-free survival prognosis, to detect the fraction of patients undergoing a high risk of relapse.

Metal-catalysed C-C bond formation at cyclopropanes.

Cyclopropanes are important substructures in natural products and pharmaceuticals. Although traditional methods for their incorporation rely on cyclopropanation of an existing scaffold, the advent of transition-metal catalysis has enabled installation of functionalized cyclopropanes using cross-coupling reactions. The unique bonding and structural properties of cyclopropane render it more easily functionalized in transition-metal-catalysed cross-couplings than other C(sp3) substrates. The cyclopropane coupling partner can participate in polar cross-coupling reactions either as a nucleophile (organometallic reagents) or as an electrophile (cyclopropyl halides). More recently, single-electron transformations featuring cyclopropyl radicals have emerged. This Review will provide an overview of transition-metal-catalysed C-C bond formation reactions at cyclopropane, covering both traditional and current strategies, and the benefits and limitations of each.

Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives.

There is an increasing interest in cyclobutanes within the medicinal chemistry community. Therefore, methods to prepare cyclobutanes that contain synthetic handles for further elaboration are of interest. Herein, we report a new approach for the synthesis of 3-borylated cyclobutanols via a formal [3 + 1]-cycloaddition using readily accessible 1,1-diborylalkanes and epihalohydrins or epoxy alcohol derivatives. 1-Substituted epibromohydrin starting materials provide access to borylated cyclobutanols containing substituents at three of the four positions on the cyclobutane core, and enantioenriched epibromohydrins lead to enantioenriched cyclobutanols with high levels of enantiospecificity (>98%). Finally, derivatization studies demonstrate the synthetic utility of both the OH and Bpin handles.

Chromatin-associated YTHDC1 coordinates heat-induced reprogramming of gene expression.

Heat stress (HS) induces a cellular response leading to profound changes in gene expression. Here, we show that human YTHDC1, a reader of N6-methyladenosine (m6A) RNA modification, mostly associates to the chromatin fraction and that HS induces a redistribution of YTHDC1 across the genome, including to heat-induced heat shock protein (HSP) genes. YTHDC1 binding to m6A-modified HSP transcripts co-transcriptionally promotes expression of HSPs. In parallel, hundreds of the genes enriched in YTHDC1 during HS have their transcripts undergoing YTHDC1- and m6A-dependent intron retention. Later, YTHDC1 concentrates within nuclear stress bodies (nSBs) where it binds to m6A-modified SATIII non-coding RNAs, produced in an HSF1-dependent manner upon HS. These findings reveal that YTHDC1 plays a central role in a chromatin-associated m6A-based reprogramming of gene expression during HS. Furthermore, they support the model where the subsequent and temporary sequestration of YTHDC1 within nSBs calibrates the timing of this YTHDC1-dependent gene expression reprogramming.

Ni-Catalyzed Reductive Cross-Coupling of Cyclopropylamines and Other Strained Ring NHP Esters with (Hetero)Aryl Halides.

A nickel-catalyzed reductive cross-coupling of cyclopropylamine NHP esters with (hetero)aryl halides is reported. This efficient protocol provides direct access to 1-arylcyclopropylamines, a bioisosteric motif commonly used in small molecule drug discovery. The reaction proceeds rapidly (<2 h) with excellent functional group tolerance and without requiring heat- or air-sensitive reagents. The method can also be extended to the arylation of four-membered strained rings. The NHP esters are easily obtained from the corresponding commercially available carboxylic acids in one step with high yields and no column chromatography.

Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.

In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.

Safe, selective, and scalable carbenes.

The synthesis of reactive carbene intermediates is made simpler and safer.

Synthesis of 1- and 1,2-Substituted Cyclopropylamines from Ketone Homoenolates.

Ketone homoenolates are intermediates with both nucleophilic and electrophilic properties. While there are several reports on their use as nucleophiles, there are few reports on their potential as electrophiles. Herein, we report the use of ketone zinc/copper homoenolates as electrophiles in the synthesis of 1- and 1,2-substituted cyclopropylamines. We found that CuCN·2LiCl is essential to produce a more reactive homoenolate intermediate. We also report a facile telescoped sequence from ß-substituted enones toward 1,2-disubstituted cyclopropylamines.

CACHE (Critical Assessment of Computational Hit-finding Experiments): A public-private partnership benchmarking initiative to enable the development of computational methods for hit-finding.

One aspirational goal of computational chemistry is to predict potent and drug-like binders for any protein, such that only those that bind are synthesized. In this Roadmap, we describe the launch of Critical Assessment of Computational Hit-finding Experiments (CACHE), a public benchmarking project to compare and improve small molecule hit-finding algorithms through cycles of prediction and experimental testing. Participants will predict small molecule binders for new and biologically relevant protein targets representing different prediction scenarios. Predicted compounds will be tested rigorously in an experimental hub, and all predicted binders as well as all experimental screening data, including the chemical structures of experimentally tested compounds, will be made publicly available, and not subject to any intellectual property restrictions. The ability of a range of computational approaches to find novel binders will be evaluated, compared, and openly published. CACHE will launch 3 new benchmarking exercises every year. The outcomes will be better prediction methods, new small molecule binders for target proteins of importance for fundamental biology or drug discovery, and a major technological step towards achieving the goal of Target 2035, a global initiative to identify pharmacological probes for all human proteins.