Synthesis and Evaluation of a Class of Compounds Inhibiting the Growth of Stromal Antigen 2 (STAG2)-Mutant Ewing Sarcoma Cells.

STAG2 (SA2) is a critical component of the cohesin complex that regulates gene expression and the separation of sister chromatids in cells. Mutations in STAG2 have been identified in over thirty different types of cancers including myeloid leukaemia, non-small cell lung, bladder and Ewing sarcoma. Selectively inhibiting cancer cells lacking of STAG2 is an attractive approach for the cancer therapy.

Diastereoselective Rhodium Catalyzed [4 + 2] Cycloisomerization of Allenes.

A diastereoselective [4 + 2] cycloisomerization of asymmetric allenyl dienes is reported. The asymmetric dienyl allenes are synthesized using the method reported by Ma. These substrates readily undergo diastereoselective intramolecular rhodium catalyzed [4 + 2] cycloisomerization analogous to thermal intramolecular Diels-Alder reactions.

Screening of Focused Compound Library Targeting Liver X Receptors in Pancreatic Cancer Identified Ligands with Inverse Agonist and Degrader Activity.

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation.

Correction: Diastereoselective synthesis of 1,3-disubstituted isoindolines and sultams via bronsted acid catalysis.

Correction for 'Diastereoselective synthesis of 1,3-disubstituted isoindolines and sultams via bronsted acid catalysis' by Ye Tao et al., Chem. Commun.

Stability and pharmacokinetics of separase inhibitor-Sepin-1 in Sprague-Dawley rats.

Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide) is a potent separase inhibitor that impedes cancer cell growth, cell migration, and wound healing, suggesting that Sepin-1 possesses a great potential to target separase-overexpressing tumors. As a part of the IND-enabling studies to bring Sepin-1 to clinic, herein we report the results from a 28-day repeat-dose pharmacokinetic study of Sepin-1 in rats.

and Analyses of Novel Peptidomimetic Disruptors for the Serotonin 5-HT Receptor Interaction With Phosphatase and Tensin Homolog.

Hypofunction of the serotonin (5-HT) 5-HT receptor (5-HTR) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HTR signaling display therapeutic potential. In the present study, we show that disruption of the 5-HTR interaction with the protein phosphatase and tensin homolog (PTEN) peptidomimetics enhances 5-HTR-mediating signaling and potentiates selective 5-HTR agonists in behavioral rodent models.

Discovery of vascular Rho kinase (ROCK) inhibitory peptides.

Unlabelled: Rho-activated kinases (ROCKs) regulate many cellular functions such as proliferation, migration, and smooth muscle contractility, but they are also associated with pathogenesis of many human diseases such as heart failure and hypertension. We used phage display libraries to identify inhibitory polypeptides that bind to the ROCK1 catalytic domain, but do not compete with the ATP-binding pocket, by screening in the presence of high ATP concentrations (1 mM). Peptide7, a promising ROCK inhibitory peptide for both ROCK isoforms, measured at 1.

Diastereoselective synthesis of 1,3-disubstituted isoindolines and sultams via bronsted acid catalysis.

The bis(trifluoromethane)sulfonimide (Tf2NH) catalyzed intramolecular hydroamidation of terminal alkynes is reported. The combination of Et3SiH and Tf2NH provides cis-1,3-disubstituted isoindolines and sultams in high yield (up to 98%) and high diastereoselectivity (up to 99 : 1 d.r.

Biophysical validation of serotonin 5-HT2A and 5-HT2C receptor interaction.

The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) in the central nervous system are implicated in a range of normal behaviors (e.g., appetite, sleep) and physiological functions (e.

The Metabolism of Separase Inhibitor Sepin-1 in Human, Mouse, and Rat Liver Microsomes.

Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug-drug interactions.

Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT receptor (5-HTR) antagonist M100907.

The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling.

Novel Bivalent 5-HT Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo.

The 5-HT receptor (5-HTR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HTR:5-HTR homodimer in these disorders are necessary. We chemically modified the selective 5-HTR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HTR:5-HTR homodimer function.

Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT Receptor Agonist.

The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of the known selective serotonin (5-HT) 5-HT receptor (5-HTR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules, as well as immobilization agents to the parent molecule with the maintenance of agonist activity. This goal was accomplished by the synthesis of novel molecules in which sites a-d were modified and resulting compounds were analyzed pharmacologically in vitro.

Synthesis and activity of benzimidazole-1,3-dioxide inhibitors of separase.

Due to the oncogenic activity of cohesin protease, separase in human cancer cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors. Herein, we report the synthesis, structural information, and structure-activity relationship (SAR) of separase inhibitors based on modification of the lead molecule 2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide, named Sepin-1, (1) identified from a high-throughput-screen. Replacement of -NO2 at C5 with other functional groups reduce the inhibitory activity in separase enzymatic assay.

Enantioselective Synthesis of (-)-Dysiherbaine.

Dysiherbaine, a natural product isolated from the Marine sponge Dysidea herbacea, has been shown to be a selective agonist of non-NMDA type glutamate receptors, kainate receptors. An enantioselective synthesis of dysiherbaine is reported. Metathesis of the diene followed by conversion of the resulting alkene to the amino alcohol and addition of the amino acid provides the natural product.

[4+2+2] Cycloaddition catalyzed by a new cationic rhodium-bisphosphine monooxide complex.

A rhodium-BozPHOS based complex is reported. This complex is competent in catalyzing the [4+2+2] cycloisomerization of cyclooctatrienes in moderate to good yields. The X-ray crystal structure of this complex is reported, along with formation of both bicyclic and tricyclic cyclooctatrienes.

Synthesis of proline-based N-heterocyclic carbene ligands.

The synthesis of proline-based N-heterocyclic carbene ligands is reported. An approach to a variety of proline-containing imidazolium NHC precursors is presented. The proline amino acids are shown to be compatible with peptide synthetic methods by incorporation into tripeptides.

Synthesis of a 2(1H)-pyridone library via rhodium-catalyzed formation of isomunchones.

Through the use of the dipolar cycloaddition of isomunchones with olefins the 2(1H)-pyridone ring system has been synthesized. (1) The use of different cyclization partners followed by diversification of the initial scaffold has provided libraries of 4-hydroxy-2(1H)-pyridones. There are no examples of this ring system in either PubChem or the MLSMR.

Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior.

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R.

Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay.

Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor.

Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity.

Synthesis and evaluation of dimeric derivatives of 5-HT(2A) receptor (5-HT(2A)R) antagonist M-100907.

It is now well accepted that at least some serotonin receptors exist in dimeric and oligmeric forms. The linking of receptor ligands has been shown to have potential in the development of selective agonists and antagonists for traditionally refractive receptors. Here we report the development of a dimeric version of the known 5-HT(2A)R antagonist, M-100907.

Structure-based redesign of an edema toxin inhibitor.

Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15μg/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin (ET)-catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.

Design, synthesis, and diversification of 3,5-substituted enone library.

This paper describes the synthesis of a 300 member library of 3,5-substituted enones. The synthesis starts with 6 different bromoenones that are accessed from the corresponding 1,3 diones. These bromides are then diversified by Suzuki coupling with a variety of aromatic and vinyl boronic acids.