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Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

The gastrointestinal tract is enriched with xenobiotic processing proteins that play important roles in xenobiotic bioactivation, metabolism, and detoxification. The application of genetically modified mouse models has been instrumental in characterizing the function of xenobiotic processing genes (XPG) and their proteins in drug metabolism. Here, we report the utilization of three-dimensional crypt organoid cultures from these animal models to study intestinal drug metabolism and toxicity. With the successful culturing of crypt organoids, we profiled the abundance of Phase I and Phase II XPG expression, drug transporter gene expression, and xenobiotic nuclear receptor (XNR) gene expression. Functions of XNRs were examined by treating crypt cells with XNR prototypical agonists. Real-time quantitative polymerase chain reaction demonstrated that the representative downstream target genes were induced. These findings were validated from cultures developed from XNR-null mice. In crypt cultures isolated from Pxr-/- mice, pregnenolone 16α-carbonitrile failed to induce Cyp3a11 gene expression; similarly, WY14643 failed to induce Cyp4a10 in the Pparα-/- crypts. Crypt cultures from control (Ugt1F/F ) and intestinal epithelial cell (IEC) specific Ugt1 null mice (Ugt1ΔIEC ) were treated with camptothecin-11, an anticancer prodrug with severe intestinal toxicity that originates from insufficient UGT1A1-dependent glucuronidation of its active metabolite SN-38. In the absence of Ugt1 gene expression, Ugt1ΔIEC crypt cultures exhibit very limited production of SN-38 glucuronide, concordant with increased apoptosis in comparison with Ugt1F/F crypt cultures. This study suggests crypt organoid cultures as an effective in vitro model for studying intestinal drug metabolism and toxicity.

Reference EPFL-ARTICLE-229716doi:10.1073/pnas.1705671114View record in Web of Science Record created on 2017-07-10, modified on 2017-07-10

Severe neonatal hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. Humanized UGT1 (hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes hyperbilirubinemia in hUGT1 neonates because of intestinal UGT1A1 gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated in hUGT1 mice with targeted deletion of intestinal IKKβ. Physiological events during neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and hyperbilirubinemia.

The conversion of simple, easily available urea-substituted 3-phenylpropargyl alcohols catalyzed by a simple IPr-gold(I) catalyst in a gold(I)-catalyzed cascade reaction composing of a gold-catalyzed nucleophilic addition and a subsequent gold-catalyzed substitution reaction delivers 1H-imidazo[1,5-a]indol-3(2H)-ones. Other gold(I) catalysts or silver catalysts gave lower yields and often gave other side products. Gold(III) and copper(II) catalysts decomposed the starting material. Twelve examples, including donor and acceptor substituents on the distal nitrogen of the urea substructure, are provided. An X-ray crystal structure analysis confirmed the structural assignment. The mechanistic investigation including isolation and further conversion of intermediates and reactions with enantiopure starting materials indicated that after the nucleophilic-addition step, the substrate undergoes an S(N)1-type benzylic substitution reaction at the indolyl alcohol intermediate or an intramolecular hydroamination reaction of the 2-vinylindole intermediate.

A wide range of highly substituted cyclopentadienes can be synthesized under mild reaction conditions and with complete atom economy.

A detailed study of the gold-catalyzed tandem 1,3-carboxy migration/allene-enyne cycloisomerization was undertaken. It was found that after the initial allene formation the selectivity of the reaction is strongly influenced by the polarization of the remaining alkyne. Depending on the substitution pattern of the starting diynes, either a Schmittel- or a Myers-Saito-type cyclization was triggered. The 6-endo-dig Myers-Saito-type cyclization gave access to benzo[b]fluorenes, while the Schmittel pathway (5-exo-dig) delivered benzofulvenes as final products. In special cases a yet unknown pathway was opened by the ambiphilic nature of the allene moiety. In these cases completely different products were obtained by the nucleophilic attack of the alkyne moiety onto the allene that can also act as an electrophile. Mechanistic studies revealed that diradical pathways can be ruled out for this type of tandem cyclization reactions and it is shown that both steps of the reaction cascade are catalyzed by the gold complex.

Application of this method is demonstrated by the first total synthesis of Reticuol (VIII).

3-Formylfuran derivatives are core structures of a variety of bioactive natural products. However, procedures for their preparation are still rare and generally inefficient in terms of atom economy: These methods require multiple steps or harsh reaction conditions and show selectivity problems. An efficient gold(I)-catalyzed cascade reaction that leads to 3-formylfurans from easily accessible starting materials is now described. A wide variety of 3-formylfurans were obtained from the corresponding symmetric and unsymmetric 1,4-diyn-3-ols in the presence of an N-oxide in good to excellent yields. Isotope-labeling experiments as well as DFT calculations support a mechanism in which, after an initial oxygen transfer, a 1,2-alkynyl migration is favored over a hydride shift; a cyclization ensues to afford the desired functionalized furan core.

The title synthesis starts from simple, easily available urea-substituted 3-phenylpropargyl alcohols.

Dibenzocycloheptatrienes are obtained by a gold-catalyzed 7-exo-dig hydroarylation protocol in a highly efficient manner. The gold-catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and efficient access to dibenzocycloheptanoids, which are an interesting and unique class of natural products. This was underlined by the first total synthesis of reticuol.

Over the past few years new synthetic methodologies for the preparation of ynamides have led to a huge increase in their use as highly variable building blocks in organic synthesis. Owing to the presence of an electron-withdrawing group ynamides show a perfect balance between stability and reactivity. Furthermore, due to their strongly polarized triple bond, ynamides show a large variety of reactions possibilities. Among these there are, for example, addition at the αor β-position, cycloaddition, ring-closing metathesis, cycloisomerization. Figure 1 shows the reactivity of ynamides bearing an electron-withdrawing group.

3-Formylfuran derivatives are core structures of a variety of bioactive natural products. However, procedures for their preparation are still rare and generally inefficient in terms of atom economy: These methods require multiple steps or harsh reaction conditions and show selectivity problems. An efficient gold(I)-catalyzed cascade reaction that leads to 3-formylfurans from easily accessible starting materials is now described. A wide variety of 3-formylfurans were obtained from the corresponding symmetric and unsymmetric 1,4-diyn-3-ols in the presence of an N-oxide in good to excellent yields. Isotope-labeling experiments as well as DFT calculations support a mechanism in which, after an initial oxygen transfer, a 1,2-alkynyl migration is favored over a hydride shift; a cyclization ensues to afford the desired functionalized furan core.

A wide range of highly substituted cyclopentadienes can be synthesized under mild reaction conditions and with complete atom economy.

International audience; We report the synthesis of novel chiral catanionic liquid crystals bearing camphorsulfonamide substructures. The phase behaviour of these long-chain substituted imidazolium sulphates and sulfonates was investigated using X-ray diffraction (XRD), polarizing optical microscopy (POM) and differential scanning calorimetry (DSC). We observed that the phase behaviour clearly depends on the substitution of both cation and anion. The chiral camphorsulfonamide substructures have an unfavourable influence on the formation of liquid crystalline (LC-) phases. Contrary to N,N0-di-alkyl-imidazolium salts, the formation of LC phases was only observed when both cation and anion are substituted with long alkyl chains (C12 or C16). Furthermore, the phase transition temperatures depend on the chain length of the alkyl groups, as higher phase transition temperatures were observed for compounds bearing longer alkyl chains. However, no macroscopic evidence for the formation of chiral mesophases was obtained.