Carbocycle synthesis via novel organopalladium addition to nitriles

Rarely observed carbopalladation of the cyano group has been investigated. Synthetic methodology for 2,3-diarylindenones by the palladium-catalyzed annulation of alkynes with 2-iodoarenenitriles has been developed. This methodology has also been adapted to the annulation of bicyclic olefins. The reaction affords 2,3-diarylindenones and polycyclic aromatic ketones in very good to excellent yields and tolerates a number of functional groups, making it an efficient synthetic route to these compounds. The reaction is believed to proceed via (1) oxidative addition of the aryl iodide to Pd(0), (2) arylpalladium addition to the carbon-carbon multiple bond, (3) addition of the resulting vinylic or alkylpalladium species across the triple bond of the cyano group to produce an iminopalladium moiety, and (4) hydrolysis of the imine intermediate. A model accounting for the electronic effects of substituents on the aromatic ring of the nitrile has also been proposed.;The palladium-catalyzed annulation of alkynes with iodoarenes containing a cyano group has been extended to the synthesis of 3,4-disubstituted 2-aminonaphthalenes. (2-Iodophenyl)-acetonitrile reacts with a variety of internal alkynes to afford 2-aminonaphthalenes in high yields. In many cases, the regioselectivity of this reaction is excellent. The scope and limitations of this process, which proceeds via a mechanism similar to the reaction between 2-iodoarenenitriles and alkynes, have been studied. When introduced into the reaction, certain hindered propargylic alcohols have been found to afford 1,3-benzoxazine derivatives rather than the expected 2-aminonaphthalenes. The involvement of trialkylamine bases in the formation of these heterocyclic compounds has been established and a mechanism for this transformation has been proposed.;A general and efficient procedure for the synthesis of 2,2-disubstituted indanones by the palladium-catalyzed cyclization of 3-(2-iodoaryl)propanenitriles has been developed. This process is also based on intramolecular carbopalladation of the cyano group. A variety of indanones have been prepared in high yields from readily available starting materials containing various functional groups that are compatible with the reaction conditions. The reaction is not limited to the synthesis of indanones as other benzocyclic ketones, as well as a number of substituted cyclopentenones, have been synthesized by this methodology

Highly Efficient Ruthenium Catalysts for the Formation of Tetrasubstituted Olefins via Ring-Closing Metathesis

A series of ruthenium-based metathesis catalysts with N-heterocyclic carbene (NHC) ligands have been prepared in which the N-aryl groups have been changed from mesityl to mono-ortho-substituted phenyl (e.g., tolyl). These new catalysts offer an exceptional increase in activity for the formation of tetrasubstituted olefins via ring-closing metathesis (RCM), while maintaining high levels of activity in ring-closing metathesis (RCM) reactions that generate di- and trisubstituted olefins

Cysteine Modifiers Suggest an Allosteric Inhibitory Site on the CAL PDZ Domain

Protein–protein interactions have become attractive targets for both experimental and therapeutic interventions. The PSD-95/Dlg1/ZO-1 (PDZ) domain is found in a large family of eukaryotic scaffold proteins that plays important roles in intracellular trafficking and localization of many target proteins. Here, we seek inhibitors of the PDZ protein that facilitates post-endocytic degradation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR): the CFTR-associated ligand (CAL). We develop and validate biochemical screens and identify methyl-3,4-dephostatin (MD) and its analog ethyl-3,4-dephostatin (ED) as CAL PDZ inhibitors. Depending on conditions, MD can bind either covalently or non-covalently. Crystallographic and NMR data confirm that MD attacks a pocket at a site distinct from the canonical peptide-binding groove, and suggests an allosteric connection between target residue Cys319 and the conserved Leu291 in the GLGI motif. MD and ED thus appear to represent the first examples of small-molecule allosteric regulation of PDZ:peptide affinity. Their mechanism of action may exploit the known conformational plasticity of the PDZ domains and suggests that allosteric modulation may represent a strategy for targeting of this family of protein–protein binding modules

First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors

Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli

Role of PLEXIND1/TGFβ signaling axis in pancreatic ductal adenocarcinoma progression correlates with the mutational status of KRAS

PLEXIND1 is upregulated in several cancers, including pancreatic ductal adenocarcinoma (PDAC). It is an established mediator of semaphorin signaling, and neuropilins are its known coreceptors. Herein, we report data to support the proposal that PLEXIND1 acts as a transforming growth factor beta (TGFβ) coreceptor, modulating cell growth through SMAD3 signaling. Our findings demonstrate that PLEXIND1 plays a pro-tumorigenic role in PDAC cells with oncogenic KRAS (KRASmut). We show in KRASmut PDAC cell lines (PANC-1, AsPC-1,4535) PLEXIND1 downregulation results in decreased cell viability (in vitro) and reduced tumor growth (in vivo). Conversely, PLEXIND1 acts as a tumor suppressor in the PDAC cell line (BxPC-3) with wild-type KRAS (KRASwt), as its reduced expression results in higher cell viability (in-vitro) and tumor growth (in vivo). Additionally, we demonstrate that PLEXIND1-mediated interactions can be selectively disrupted using a peptide based on its C-terminal sequence (a PDZ domain-binding motif), an outcome that may possess significant therapeutic implications. To our knowledge, this is the first report showing that (1) PLEXIND1 acts as a TGFβ coreceptor and mediates SMAD3 signaling, and (2) differential roles of PLEXIND1 in PDAC cell lines correlate with KRASmut and KRASwt status

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. Conclusions: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes

Carbocycle synthesis via novel organopalladium addition to nitriles

Rarely observed carbopalladation of the cyano group has been investigated. Synthetic methodology for 2,3-diarylindenones by the palladium-catalyzed annulation of alkynes with 2-iodoarenenitriles has been developed. This methodology has also been adapted to the annulation of bicyclic olefins. The reaction affords 2,3-diarylindenones and polycyclic aromatic ketones in very good to excellent yields and tolerates a number of functional groups, making it an efficient synthetic route to these compounds. The reaction is believed to proceed via (1) oxidative addition of the aryl iodide to Pd(0), (2) arylpalladium addition to the carbon-carbon multiple bond, (3) addition of the resulting vinylic or alkylpalladium species across the triple bond of the cyano group to produce an iminopalladium moiety, and (4) hydrolysis of the imine intermediate. A model accounting for the electronic effects of substituents on the aromatic ring of the nitrile has also been proposed.;The palladium-catalyzed annulation of alkynes with iodoarenes containing a cyano group has been extended to the synthesis of 3,4-disubstituted 2-aminonaphthalenes. (2-Iodophenyl)-acetonitrile reacts with a variety of internal alkynes to afford 2-aminonaphthalenes in high yields. In many cases, the regioselectivity of this reaction is excellent. The scope and limitations of this process, which proceeds via a mechanism similar to the reaction between 2-iodoarenenitriles and alkynes, have been studied. When introduced into the reaction, certain hindered propargylic alcohols have been found to afford 1,3-benzoxazine derivatives rather than the expected 2-aminonaphthalenes. The involvement of trialkylamine bases in the formation of these heterocyclic compounds has been established and a mechanism for this transformation has been proposed.;A general and efficient procedure for the synthesis of 2,2-disubstituted indanones by the palladium-catalyzed cyclization of 3-(2-iodoaryl)propanenitriles has been developed. This process is also based on intramolecular carbopalladation of the cyano group. A variety of indanones have been prepared in high yields from readily available starting materials containing various functional groups that are compatible with the reaction conditions. The reaction is not limited to the synthesis of indanones as other benzocyclic ketones, as well as a number of substituted cyclopentenones, have been synthesized by this methodology.</p