Gut Microbiome: Profound Implications For Diet And Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease

A Lifetime Of Chemical Exposure - Dangers To Human Health

Dr. Cory Theberge, from UNE\u27s College of Pharmacy, gives an overview of contaminants of emerging concern in the environment, how they end up there, and the scope of the problem in the United States. Dr. Richard Peterson, from UNE\u27s Department of Environmental Studies, introduces the presentation.https://dune.une.edu/pharmsci_facpres/1000/thumbnail.jp

Chain Extension of Amino Acid Skeletons: Preparation of Ketomethylene Isosteres

Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension reaction in which a variety of amino acid-derived β-keto esters are converted to γ-keto esters in a single step. The reaction tolerates a variety of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter

A Divergent Diastereoselective Approach to Bicyclopropanes

The diastereoselective cyclopropanation of three stereoisomerically unique vinylcyclopropanes was studied. The selective preparation of six stereoisomeric bicyclopropanes was accomplished by an iterative reagent-controlled process. With the exception of the cis-syntrans-bicyclopropane, all isomers can be prepared in a diastereomeric excess of greater than 5:1

Diastereoselective Synthesis of Bicyclopropanes

Diastereoselective cyclopropanation of a trans-substituted vinyl cyclopropane was studied. The stereochemistry of the major and minor isomers was assigned by diastereoselective synthesis of the two isomers

Studies on the Diastereoselective Preparation of Bicyclopropanes

The identification of two natural products, FR-900848 and U-106305, has stimulated interest concerning the relationship between configurational isomerism, conformational isomerism, and biological activity of polycyclopropanes. Efforts to investigate the relationship between configurational and conformational isomerism through molecular modeling suggest that significantly different three-dimensional structures will result from unique primary structures. Any effort to address these issues demands that stereoselective methods for the preparation of polycyclopropanes be developed. We have investigated the application of zinc−carbenoid cyclopropanation in the presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopropanes. The trans-vinylcyclopropane starting materials demonstrated very little substrate-induced stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol. A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate

Ylide-Mediated Bis-Cyclopropane Formation: A Reversal in Substrate-Mediated Facial Selectivity

The substrate-based stereocontrol observed in the sulfur ylide mediated cyclopropanation of cis-β-cyclopropyl-α,β-unsaturated esters is complementary to that observed with zine-carbenoids. The selectivity for preparation of the cis-syn-trans-bis-cyclopropane, although modest, is superior to previous substrate and reagent-mediated processes

Stereoselective Formation of a Functionalized Dipeptide Isostere by Zinc Carbenoid-mediated Chain Extension

The application of a zinc carbenoid-mediated chain-extension reaction to a functionalized peptide isostere is reported. The cleavage site of human CVM protease was utilized as a target for testing the synthetic methodology. The utility of this chain-extension reaction is demonstrated in the preparation of an amino acid-derived α-unsubstituted γ-keto ester, which is incorporated into a framework that mimics a tetrapeptide. The identification of a suitable protecting group strategy facilitated the application of a tandem reaction for the incorporation of an α-side chain, and the use of an oxazolidinone auxiliary provided excellent diastereocontrol in a tandem chain-extension−aldol reaction. Stereoselectivity of the tandem chain-extension−aldol reaction was determined through application of a CAN-mediated oxidative cleavage reaction

Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A <i>K</i>_i of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound <b>15h</b>, with PDE10A <i>K</i>_i of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing