An air-stable cationic Au(I) complex featuring a Z-type ligand (boron atom) as a σ-acceptor was developed for elucidating the effect of B on catalytic reactions. An enyne cyclization in the presence of either [Au→B](+) or [Au](+) showed that [Au→B](+) promotes the reactivity, which enabled the effective construction of not only five- and six-membered rings, but also seven-membered rings.

Emission gas and air contain not only CO but also plentiful moisture, making it difficult to achieve selective CO absorption without hydration. To generate absorbed CO (wet CO) under heating, the need for external energy to release the absorbed water has been among the most serious problems in the fields of carbon dioxide capture and storage (CCS) and direct air capture (DAC). We found that the introduction of the hydrophobic phenyl group into alkylamines of CO absorbents improved the absorption selectivity between CO and water. Furthermore, ortho-, meta-, and para-xylylenediamines (OXDA, MXDA, PXDA, respectively) absorbed only CO in air without any hydration. Notably, MXDA·CO was formed as an anhydrous carbamic acid even in water, presumably because it was covered with hydrophobic phenyl groups, which induces a reverse lipid bilayer structure. Dry CO was obtained from heating MXDA·CO at 103-120 °C, which was revealed to involve chemically the Grignard reaction to form the resulting carboxylic acids in high yields.

The unprecedented C(sp(3))-C(sp(3)) bond cleavage of unactivated cyclopentane has been achieved. Rh(I)-catalyzed cycloaddition of allenylcyclopentane-alkynes produced in situ the 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediates, which subsequently underwent [7+2] cycloaddition via β-C elimination, affording bicyclo[7.4.0]tridecatriene derivatives in good yields. Changing the Rh(I) catalyst effected the Cγ-H bond activation of the common 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediate to produce the novel spiro[2.4]heptane skeleton in a site-selective manner.

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

ABSTRACT:Many anti-human immunodeficiency virus 1 nucleoside reverse-transcriptase inhibitors have low central nervous system (CNS) distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein breast cancer resistance protein (Bcrp) 1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1 Nucleoside analog reverse transcriptase inhibitors (NRTIs) continue to be a vital and effective component of combinatorial antiretroviral therapy (ART) for treating HIV infection (Dieterich, 2006). However, the CNS penetration of a number of NRTIs has been found to be low. The limited entry of these drugs into the brain has been attributed to the tight junctions and active efflux transport mechanisms at the blood-brain barrier (BBB) (Sawchuk and Yang, 1999). The specific mechanisms, i.e., BBB efflux transporters that contribute to the reduced CNS exposure of these anti-HIV agents need to be determined to yield insight into how one can improve their targeted bioavailability to the brain, an important pharmacological sanctuary site for the virus.Efflux transport proteins, such as P-glycoprotein (P-gp) and the Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.020974.ABBREVIATIONS: NRTI, nucleoside analog reverse transcriptase inhibitor; ART, antiretroviral therapy; HIV, human immune deficiency virus; CNS, central nervous system; BBB, blood-brain barrier; P-gp, P-glycoprotein; MRP/Mrp, multidrug resistance-associated protein; ABC, abacavir, (1S,4R)-4[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol); MDR/mdr, multidrug resistance; MDCK, Madin-Darby canine kidney; BCRP/Brcp, breast cancer resistance protein; AZT, zidovudine, 3-azido-3-deoxythymidine; 3TC, 2Ј,3Ј-dideoxy-3Ј-thiacytidine; d4T, stavudine, 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxythymidine; ddI, 2Ј, 3Ј-dideoxyinosine; GF120918, N[4[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide); Ko143,2,3,4,6,7,12,2Ј:1,6]pyrido [3,4-b]indol-3-yl)-propionic acid tert-butyl ester; ADME, absorption, distribution, metabolism, and excretion; AUC plasma , area under the concentration-time profile for plasma; AUC brain , area under the concentration-time profiles for brain; LY33579, (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-␣-((5-quinoloyloxy)methyl)-1-piperazineethanol trihydrochloride; ddC,2Ј,3Ј-dideoxycytidine; NIH, National Institutes of Health; HPLC, high-performance liquid chromatography; PBS, phosphate-buffered saline.