No abstract

The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).

No abstract

The C-F bond is the strongest single bond in organic compounds. It is the most challenging task to study the activation of C-F bond in organic synthesis. Trifluoromethyl-containing compounds, which...

No abstract

The Heihe River Basin (HRB) is a typical arid inland river basin in northwestern China. From the 1960s to the 1990s, the downstream flow in the HRB declined as a result of large, artificial changes in the distribution of water and land and a lack of effective water resource management. Consequently, the ecosystems of the lower reaches of the basin substantially deteriorated. To restore these degraded ecosystems, the Ecological Water Diversion Project (EWDP) was initiated by the Chinese government in 2000. The project led to agricultural and ecological changes in the middle reaches of the basin. In this study, we present three datasets of land use/cover in the middle reaches of the HRB derived from Landsat TM/ETM+ images in 2000, 2007 and 2011. We used these data to investigate changes in land use/cover between 2000 and 2011 and the implications for sustainable water resource management. The results show that the most significant land use/cover change in the middle reaches of the HRB was the continuous expansion of farmland for economic interests. From 2000 to 2011, the farmland area increased by 12.01%. The farmland expansion increased the water resource stress; thus, groundwater was over-extracted and the ecosystem was degraded in particular areas. Both consequences are negative and potentially threaten the sustainability of the middle reaches of the HRB and the entire river basin. Local governments should therefore improve the management of water resources, particularly groundwater management, and should strictly control farmland reclamation. Then, water resources could be ecologically and socioeconomically sustained, and the balance between upstream and downstream water demands could be ensured. The results of this study can also serve as a reference for the sustainable management of water resources in other arid inland river basins.

All products of the dirhodium tetraacetate catalyzed reactions of ethyl diazoacetate with furan, 2-methylfuran, 2,5-dimethylfuran, 2-ra-octylfuran, methyl furcate and methyl /3-(«-furyl)acrylate were isolated and characterized. They consist mostly of exo-cyclopropanecarboxylates and 1,4-diacyl-1,3-butadienes and some 3-(acylmethyl)furans. Treatment of the crude reaction mixtures with iodine or boron trifluoride furnishes 1,4-diacyl-1 (E) ,3 (E)-butadienes. Horner-Emmons condensation with the latter dicarbonyl compounds leads to l,6-diacyl-l,3,5-hexatrienes. Proper combinations of methyl -diazopropionate, furans, and -phosphono esters afford segments of retinol and /3-carotene, while combinations of -diazo ketones, furans, and «-phosphono ketones yield LTB3-like leukotrienes. Finally, dirhodium tetraacetate promoted decomposition of ethyl diazoacetate in l,2-bis(2-furyl)ethane and iodine treatment gives a diketo diester, whose reduction, dehydration, and hydrolysis leads to the naturally occurring dodecahexaenic dicarboxylic acid, corticrocin.

No abstract