Recent advances in catalytic asymmetric synthesis.

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Photoreduction of Trifluoromethyl Group: Lithium Ion Assisted Fluoride-Coupled Electron Transfer from EDA Complex.

Photoinduced single-electron reduction is an efficient method for the mono-selective activation of the C-F bond on a trifluoromethyl group to construct a difluoroalkyl group. We have developed an electron-donor-acceptor (EDA) complex mediated single-electron transfer (EDA-SET) of α,α,α-trifluoromethyl arenes in the presence of lithium salt to give α,α-difluoroalkylarenes. The C-F bond reduction was realized by lithium iodide and triethylamine, two common feedstock reagents. Mechanistic studies revealed the generation of a α,α-difluoromethyl radical by single-electron reduction and defluorination, followed by the radical addition to alkenes. Lithium salt interacted with the fluorine atom to promote the photoinduced reduction mediated by the EDA complex. Computational studies indicated that the lithium-assisted defluorination and the single-electron reduction occurred concertedly. We call this phenomenon fluoride-coupled electron transfer (FCET). FCET is a novel approach to C-F bond activation for the synthesis of organofluorine compounds.

Kinetic resolution of 1,1'-binaphthyl-2,2'-diamine derivatives by chiral calcium phosphate-catalyzed acylation.

1,1'-Binaphthyl-2,2'-diamine (BINAM) is a useful axially chiral compound. The kinetic resolution of BINAM is one of the most crucial methods for synthesizing chiral BINAM. We have developed a chiral calcium phosphate-catalyzed kinetic resolution of BINAM by utilizing an acylation reaction to produce a mono-amide. The kinetic resolution of BINAM derivatives was achieved by using isobutyric anhydride in the presence of chiral calcium phosphate and 4-morpholinopyridine with up to s = 127. 6,6'-Substituted BINAM derivatives were also applicable for this reaction. The resulting mono-acylated BINAM could be transformed into BINAM by hydrolysis under acidic conditions.

Mesothelial cells with mesenchymal features enhance peritoneal dissemination by forming a protumorigenic microenvironment.

Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination.

Extracellular water to total body water ratio, a novel predictor of recurrence in patients with colorectal cancer.

Background: Total body water (TBW) fraction, which accounts for 60% of body weight, is an important indicator of body composition, and the extracellular water to TBW ratio (ECW/TBW) is reportedly useful in predicting clinical outcomes of patients with organ disorders. We aimed to clarify the clinical impact of preoperative ECW/TBW status on survival outcomes in cancer patients. Methods: We used a database of 320 colorectal cancer (CRC) patients who underwent potentially curative resections. Preoperative ECW/TBW was measured using a bioelectrical impedance analysis (BIA), and its correlation with patient survival outcomes, clinicopathological factors, laboratory data, and comorbidities were analyzed. Results: A high preoperative ECW/TBW was significantly associated with poorer relapse-free survival (RFS; p = 0.001) and overall survival (OS; p = 0.003). A high ECW/TBW ratio was significantly associated with older age (p < 0.001), low BMI (p = 0.009), and right-sided tumors (p = 0.03). In a multivariate analysis, a high ECW/TBW significantly predicted a higher RFS mortality (HR: 2.07, 95% CI: 1.10-3.88, p = 0.024) and OS mortality (HR: 3.23, 95% CI: 1.25-8.36, p = 0.016). Furthermore, a high ECW/TBW was significantly associated with lower hemoglobin (p < 0.001) and albumin levels (p < 0.001), but not comorbidities. Conclusions: A high preoperative ECW/TBW was a predictive factor for recurrence and poorer overall survival independent of the tumor, node, and metastasis (TNM) stage. Our data suggest that preoperative evaluation of ECW/TBW using BIA might serve as a novel tool for developing CRC treatment strategies.

Enantioselective synthesis of 3-(N-indolyl)quinolines containing axial and central chiralities.

Quinoline and indole are important core structures in biologically active compounds and materials. Atropisomeric biaryls consisting of quinoline and indole are a unique class of axially chiral molecules. We report herein enantioselective synthesis of 3-(N-indolyl)quinolines having both C-N axial chirality and carbon central chirality by a photoredox Minisci-type addition reaction catalyzed by a chiral lithium phosphate/Ir-photoredox complex. The catalytic system enabled access to a unique class of 3-(N-indolyl)quinolines with high chemo-, regio-, and stereoselectivities in good yields through the appropriate choice of an acid catalyst and a photocatalyst. This is the first example of the synthesis of 3-(N-indolyl)quinoline atropisomers in a highly enantioselective manner.

Visible-light-driven enantioselective intermolecular [2 + 2] photocyclization utilizing bathochromic excitation mediated by a chiral phosphoric acid.

We report herein an enantioselective intermolecular [2 + 2] photocyclization of alkenyl 2-pyrrolyl ketones using the bathochromic shift mediated by a chiral phosphoric acid. This synthetic method provides access to cyclobutanes with up to 98% ee. According to the UV-Vis spectra, the bathochromic effect was observed by mixing alkenyl 2-pyrrolyl ketones and a chiral phosphoric acid. A non-linear correlation was observed between the ee of the catalyst and the ee of the cycloadduct, suggesting that both substrates bind to the chiral phosphoric acid and form a dimer complex before photocycloaddition.

Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.

Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Chiral Phosphoric Acid-Palladium(II) Complex Catalyzed Asymmetric Desymmetrization of Biaryl Compounds by C(sp3)-H Activation.

Desymmetrization is an essential method for the synthesis of chiral compounds, particularly chiral biaryls. We have developed an enantioselective synthesis of axially chiral biaryls by desymmetrization using C(sp3)-H activation catalyzed by chiral palladium phosphate. Mechanistic studies show that C-H activation is the rate- and enantiomer-determining step. To the best of our knowledge, this is the first report of asymmetric desymmetrization of axially chiral compounds by C(sp3)-H activation.

2-Silylated Dihydroquinazolinone as a Photocatalytic Energy Transfer Enabled Radical Hydrosilylation Reagent.

The hydrosilylation of alkenes is one of the most important methods for the synthesis of organosilicon compounds. In addition to the platinum-catalyzed hydrosilylation, silyl radical addition reactions are notable as economic reactions. An efficient and widely applicable silyl radical addition reaction was developed by using 2-silylated dihydroquinazolinone derivatives under photocatalytic conditions. Electron-deficient alkenes and styrene derivatives underwent hydrosilylation to give addition products in good to high yields. Mechanistic studies indicated that the photocatalyst functioned not as a photoredox catalyst but as an energy transfer catalyst. DFT calculations clarified that the triplet excited state of 2-silylated dihydroquinazolinone derivatives released a silyl radical through the homolytic cleavage of a carbon-silicon bond, and this was followed by the hydrogen atom transfer pathway, not the redox pathway.

Enantioselective Synthesis of an All-Carbon Quaternary Stereocenter by Chiral Brønsted Acid-Catalyzed Friedel-Crafts-Type Reaction between Pyrroles and 3-Indolylmethanols.

We have developed a chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts alkylation reaction between pyrroles and indolylmethanols. Wide substrate scope was observed, and a chiral all-carbon quaternary center was constructed at the 3 position of indoles in high yields with high to excellent enantioselectivities (up to 99% ee).

The colon inflammatory index score can predict the survival outcome after resection of colorectal cancer: a retrospective multicentre study.

PURPOSE: Many systemic inflammatory markers have been identified to be prognostic factors in various diseases, including colorectal cancer (CRC). The Colon Inflammatory Index (CII), which is based on the lactate dehydrogenase (LDH) level and the neutrophil-to-lymphocyte ratio (NLR), is reportedly a predictor of the outcome of chemotherapy in patients with metastatic CRC. This retrospective review study aimed to determine whether CII can predict the prognosis after surgical resection of CRC. METHODS: A total of 1,273 patients who underwent CRC resection were enrolled and divided into a training cohort (n = 799) and a validation cohort (n = 474). The impact of the preoperative CII score on overall survival (OS) and recurrence-free survival (RFS) was assessed. RESULTS: In the training cohort, the CII score was good in 569 patients (71.2%), intermediate in 209 (26.2%), and poor in 21 (2.6%). There were significant between-group differences in body mass index, American Society of Anaesthesiologists physical status, and preoperative tumour markers. The 5-year OS rate was significantly lower in patients with an intermediate or poor CII score (CII risk) than in those with no CII risk (73.8% vs. 84.2%; p < 0.001, log-rank test). In multivariate analysis, CII risk remained a significant independent predictor of poor OS (hazard ratio 1.75; 95% confidence interval 1.18-2.60; p = 0.006). In the validation cohort, the 5-year OS rate was significantly lower in patients with CII risk than in those with no CII risk (82.8% vs. 88.4%; p = 0.046, log-rank test). CONCLUSION: These findings indicate that the CII can predict OS after resection of CRC.

The impact of the advanced lung cancer inflammation index on the outcomes of patients with metastatic colorectal cancer who receive chemotherapy.

BACKGROUND: Advanced lung cancer inflammation index (ALI) is reported to be a prognosticator in various cancer patients with chemotherapy. However, the clinical impact of the ALI on treatment strategies in metastatic colorectal cancer (mCRC) patients remains unclear. METHODS: A total of 356 patients, who received first-line chemotherapy for mCRC between April 2005 and November 2019 in a single institution, were retrospectively enrolled. The association of pretreatment ALI (calculated as follows: BMI × albumin value/neutrophil-to-lymphocyte ratio) status with clinicopathological factors and patient survival outcome was analyzed, using subgroup analysis. RESULTS: The ALI-low cases were significantly associated with female sex, more synchronous metastasis, multiple metastatic sites, less primary tumor resection, less liver resection after chemotherapy, and poor overall survival (OS). A multivariate Cox proportional hazards analysis clarified that the ALI-low status was independently associated with poor OS (HR: 1.78, 95% CI 1.27-2.48, P = 0.001), in addition to right side tumor, multiple metastatic sites, and the non-performance of liver resection after chemotherapy. A subgroup analysis revealed that primary tumor resection and the resection of liver metastases after chemotherapy could not improve the prognosis of ALI-low cases in comparison with ALI-high cases, and the type of first-line chemotherapy did not significantly affect the association between the prognosis and the ALI status. CONCLUSION: ALI comprehensively evaluates the prognostic host status and is a reliable prognosticator for the mCRC patients with chemotherapy. Calculating pretreatment ALI may serve as a cost-effective and easily available tool for constructing treatment strategies.

Stromal Reprogramming through Dual PDGFRα/ß Blockade Boosts the Efficacy of Anti-PD-1 Immunotherapy in Fibrotic Tumors.

Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRß) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti-PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/ß blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/ß blockade and anti-PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer. SIGNIFICANCE: Stromal targeting with PDGFRα/ß dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer. See related commentary by Tauriello, p. 655.

IL-1ß derived from mixed-polarized macrophages activates fibroblasts and synergistically forms a cancer-promoting microenvironment.

BACKGROUND: Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression. METHODS: Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings. RESULTS: Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1ß from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues. CONCLUSION: These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells.

A novel tdTomato transgenic mouse model to visualize FAP-positive cancer-associated fibroblasts.

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development.

Prognostic Significance of Systemic Inflammation Indices by K-ras Status in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Systemic inflammation markers are useful prognostic indicators for metastatic colorectal cancer. However, the influence of K-ras genotypes on these markers in patients with metastatic colorectal cancer is unclear. OBJECTIVE: This study aimed to evaluate the associations between systems of evaluating pretreatment systemic inflammation and outcomes according to K-ras genotypes in patients with metastatic colorectal cancer. DESIGN: This was a retrospective study. SETTINGS: This study was conducted at a university hospital. PATIENTS: This study included a total of 272 patients ( K-ras wild type: K-ras mutant = 169:103) who received first-line systemic chemotherapy for metastatic colorectal cancer. MAIN OUTCOME MEASURES: We retrospectively calculated 8 systemic inflammation indices: neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, prognostic nutritional index, Glasgow prognostic score, Naples prognostic score, systemic inflammation score, and systemic immune-inflammation index. Patients were categorized into high or low groups for each index. The prognostic relevance of these indices for overall survival was evaluated according to the K-ras genotype. RESULTS: Kaplan-Meier survival analyses showed that median overall survival significantly differed between the high and low groups for all indices in the K-ras wild-type group but not in the K-ras mutant group, except for Glasgow prognostic score and lymphocyte/monocyte ratio. Multivariate Cox regression analyses identified all indices as independent prognostic factors. In the K-ras wild-type group, all indices except platelet/lymphocyte ratio had strong prognostic effects, but not in the K-ras mutant group. Interaction tests indicated that K-ras genotype significantly influenced the prognostic impacts of the neutrophil/lymphocyte ratio ( p = 0.042), prognostic nutritional index ( p = 0.048), Naples prognostic score ( p < 0.001), and systemic immune-inflammation index ( p = 0.004). LIMITATIONS: A major limitation of this study is the lack of external validation. CONCLUSIONS: The prognostic significance of systemic inflammation indices is more useful in patients with K-ras wild-type metastatic colorectal cancer than those with K-ras mutant cancer. See Video Abstract at http://links.lww.com/DCR/B921 . IMPORTANCIA PRONSTICA DE LOS NDICES DE INFLAMACIN SISTMICA POR ESTADO DE KRAS EN PACIENTES CON CNCER COLORRECTAL METASTSICO: ANTECEDENTES:Los marcadores de inflamación sistémica son indicadores de pronósticos útiles para el cáncer colorrectal metastásico. Sin embargo, la influencia de los genotipos KRAS en estos marcadores en pacientes con cáncer colorrectal metastásico no está clara.OBJETIVO:Evaluamos las asociaciones entre los sistemas de evaluación de la inflamación sistémica previa al tratamiento y los resultados según los genotipos K-ras en pacientes con cáncer colorrectal metastásico.AJUSTE:Este estudio se realizó en un hospital universitario.DISEÑO:Este fue un estudio retrospectivo.PACIENTES:Un total de 272 pacientes (K-ras wildtype [K-raswt]:mutant [K-rasMut] = 169:103) que recibieron quimioterapia sistémica de primera línea para el cáncer colorrectal metastásico.PRINCIPALES MEDIDAS DE RESULTADO:Calculamos retrospectivamente 8 índices de inflamación sistémica: proporción de neutrófilos/linfocitos, proporción de plaquetas/linfocitos, proporción de linfocitos/monocitos, índice nutricional pronóstico, puntuación de pronóstico de Glasgow, puntuación de pronóstico de Nápoles, puntuación de inflamación sistémica e índice de inmunoinflamación sistémica. Los pacientes se clasificaron en grupos altos o bajos para cada índice. La relevancia pronóstica de estos índices para la supervivencia global se evaluó según el genotipo K-ras.RESULTADOS:Los análisis de supervivencia de Kaplan-Meier mostraron que la mediana de la supervivencia general difería significativamente entre los grupos alto y bajo para todos los índices en el grupo K-raswt pero no en el grupo K-rasMut, excepto para la puntuación de pronóstico de Glasgow y la proporción de linfocitos/monocitos. Los análisis de regresión multivariable de Cox identificaron todos los índices como factores pronósticos independientes. En el grupo K-raswt, todos los índices, excepto el cociente plaquetas/linfocitos, tuvieron fuertes efectos pronósticos, pero no en el grupo K-rasMut. Las pruebas de interacción indicaron que el genotipo K-ras influyó significativamente en los impactos pronósticos de la proporción de neutrófilos/linfocitos (p = 0,042), el índice nutricional pronóstico (p = 0,048), la puntuación pronóstica de Nápoles (p < 0,001) y el índice de inflamación inmunológica sistémica (p = 0,004).LIMITACIÓN:Una limitación importante de este estudio es la falta de validación externa.CONCLUSIÓNES:La importancia pronóstica de los índices de inflamación sistémica es más útil en pacientes con cáncer colorrectal metastásico K-raswt. Consulte Video Resumen en http://links.lww.com/DCR/B921 . (Traducción-Dr. Yolanda Colorado ).

Dual-Role Halogen-Bonding-Assisted EDA-SET/HAT Photoreaction System with Phenol Catalyst and Aryl Iodide: Visible-Light-Driven Carbon-Carbon Bond Formation.

Electron donor-acceptor (EDA) complex-mediated single-electron transfer (SET) is a crucial method for generating carbon radicals. Hydrogen atom transfer (HAT) enables the direct generation of alkyl radicals. We report a dual-role EDA-SET/HAT photoreaction system for carbon-carbon bond formation using a phenol catalyst and aryl iodide. This system facilitates addition of alkyl radicals generated from ethers, amide, sulfide, and cycloalkane to arenes. Mechanistic studies revealed that EDA complex formation is mediated by halogen bonding between phenoxide and aryl iodide. Irradiation of the EDA complex with visible light generates an aryl radical, which abstracts a hydrogen atom from an sp3 carbon to form an alkyl radical.

Tumor microenvironmental 15-PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer.

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh+/- mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh+/- mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh+/- Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion.

Enantioselective Friedel-Crafts Alkylation Reaction of Pyrroles with N-Unprotected Alkynyl Trifluoromethyl Ketimines.

Developed herein is an enantioselective Friedel-Crafts alkylation reaction of N-unprotected alkynyl trifluoromethyl ketimines with pyrroles catalyzed by chiral phosphoric acid to furnish chiral primary α-trifluoromethyl-α-(2-pyrrolyl)propargylamines with high enantioselectivity. Transformation of the alkynyl group of the adducts afforded optically active α-trifluoromethylated amines bearing various substituents such as alkyl, alkenyl, enyne, and triazole without loss of optical purity.