Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide-induced acute lung injury via anti-inflammatory actions. Thirty-three 4-amino quinazolin derivatives were synthesized and screened for anti-inflammatory activities in lipopolysaccharide-induced macrophages. The most potent four compounds, 6h, 6m, 6p, and 6q, were shown dose-dependent inhibition against lipopolysaccharide-induced TNF-α and IL-6 release. Then, the preliminary structure-activity relationship and quantitative structure-activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide-induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q, obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide-induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.

A new and efficient route for synthesis of enantiomerically pure biisoindoline and its isomer based on the diaza-Cope rearrangement reaction with chiral 1,2-bis(2-hydroxylphenyl)-1,2-diaminoethane as starting material has been developed. The newly prepared biisoindoline was employed as a chiral ligand in the Ni(II)-catalyzed enantioselective Michael addition of malonates to conjugated nitroalkenes, and good to excellent enantioselectivities were obtained.

Pancreatic cancer is the most commonly diagnosed malignancy among solid tumors and has shown an increasing trend year by year. Thus, there is an urgent need for the discovery of new anticancer drugs for the treatment of pancreatic cancer. In recent years, it has been reported that the compound HO-3867, a novel analog of the natural product curcumin, showed antitumor activity with low toxicity. However, the underlying mechanism of this compound's attack on cancer cells is not very clear. In the present study, it was found that HO-3867 showed good antitumor activity at the concentration of 2 μmol/l in PANC-1 and BXPC-3 cells. Importantly, it was also found that HO-3867 treatment significantly induced reactive oxygen species (ROS) production in human pancreatic cancer cell lines, inducing PANC-1 and BXPC-3 cells. Co-treatment with the ROS scavenger, N-acetyl cysteine, partially abrogated HO-3867-induced cell apoptosis. The activation of mitogen-activated protein kinase and endoplasmic reticulum stress indicated a downstream event of ROS generation in mediating the anticancer effect of the HO-3867. In addition, independent of the ROS pathway, direct STAT3 inhibition was observed in HO-3867-induced cell apoptosis. Taken together, the results of this work suggest that both the ROS-dependent ER stress and STAT3 pathways were implicated in the cell apoptosis induced by the novel compound HO-3867.

Organic motifs with contiguous multiple stereocenters exist in numerous natural and unnatural products that exhibit important biological activity.[1] The number of possible stereoisomers increases exponentially with the number of stereocenters, thus the highly stereoselective synthesis of chiral compounds with multiple stereocenters from simple starting materials is a challenge. Nature has developed many efficient ways to construct such structures from simple starting materials, as demonstrated by the production of chiral carbohydrates, proteins, and alkaloids. Inspired by nature, the asymmetric domino process, which generates more than one chemical bond concomitantly with the creation of multiple stereocenters in a one-pot fashion, has emerged as a promising way to achieve these aims.[2] Despite the fact that a number of structurally diverse compounds with contiguous multiple stereocenters have been synthesized using this strategy, to the best of our knowledge, a domino process which generates six or more stereocenters by one intermolecular reaction of two simple compounds in an asymmetric fashion has not been reported. [3,4] The identification of a reactive species that triggers a domino process is a prerequisite for the successful establishment of an efficient tandem reaction. As active species, enolates are considered to be the most powerful and reliable cornerstones for establishing many classical transformations.[5] a-Ketoesters could be recognized as latent enolates since the keto-to-enol tautomerization could easily take place in these compounds in the presence of suitable Lewis acids. [6] With this in mind, we envisaged that the reactive enolate species derived from an a-ketoester would be useful to trigger a formal [2+2+2] cycloaddition through an asymmetric Michael [7] /Michael/Henry [8] tandem sequence with nitroalkenes as electrophiles (Scheme 1). Mechanistically, a chiral Lewis acid catalyst would activate the a-ketoester to give rise to the intermediate enolate A which would then add to nitroalkene 2 by a conjugate addition to yield intermediate B.The intermediate B would further react with nitroalkene 2 to generate the intermediate C under appropriate reaction conditions. Ring closure through the Henry reaction would lead to the desired six-membered annulation product 3 with six stereogenic centers (Scheme 1). The challenge of designing such an efficient catalytic asymmetric strategy mainly depends on the necessity of stereoselectively generating the stable reactive species B and highly reactive intermediate C in situ. To address this challenge, we need to identify a chiral transition metal catalyst to generate the metal enolate A with stereodefined geometry, thus guaranteeing that the first conjugate Michael addition proceeds with high diastereoand enantioselectivity. A chiral Lewis acid catalyst with the appropriate steric and electronic properties is crucial for the successful implementation the above strategy. Given that a conformationally rigid structure would have good chiral induction ab...