Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors.

Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung cancer with the lowest IC50 value (0.09 µM < IC50 < 0.86 µM). Compared with CA-4, Compounds 8j and 8o displayed lower cytotoxicities toward normal cells but higher antiproliferative activities against RKO (IC50 = 0.15 µM and 0.09 µM respectively), NCI-H1299 (IC50 = 0.73 µM and 0.14 µM respectively), and A549 cells (IC50 = 0.86 µM and 0.37 µM respectively). Further investigations revealed that 8o shows higher tubulin polymerization inhibitory activity (IC50 = 3.1 ± 0.5 µM) than colchicine (IC50 = 8.6 ± 0.2 µM), and induced cell cycle arrest at the G2/M phase and cellular apoptosis through disrupting the microtubule network.

Meyer-Schuster-Type Rearrangement of Propargylic Alcohols into α-Selenoenals and -enones with Diselenides.

We describe a mild and broadly applicable protocol for the preparation of a diverse array of multisubstituted α-selenoenals and -enones from readily accessible propargylic alcohols and diselenides. The transformation proceeds via the Selectfluor-promoted selenirenium pathway, which enables selenenylation/rearrangement of a variety of propargylic alcohols. Gram-scale experiments showed the potential of this synergistic protocol for practical application.

Hydrogen Production from Formic Acid by In Situ Generated Ni/CdS Photocatalytic System under Visible Light Irradiation.

Simple and practical noble-metal-free catalyzed hydrogen production from sustainable resources, such as renewable formic acid, is highly desirable. Herein, the development of an efficient photocatalytic hydrogen production from aqueous solution of formic acid using in situ generated Ni/CdS photocatalytic system was described. CdS-Cys (Cys=l-cysteine) quantum dots (QDs) acting as photocatalyst with Ni(OAc)2 as H2 production catalyst precursor, a 94 % yield was obtained within 5 h under visible light irradiation at 50 °C. The average rate of H2 production reached up to 282 µmol mg-1 h-1 with 99.8 % H2 selectivity. Mechanistic studies indicate cooperation of dynamic quenching and static quenching of CdS-Cys QDs by Ni(OAc)2 . Especially, Ni0 , generated in the dynamic quenching, accelerated the electron transfer by acting as an electron outlet and enhancing the stability of CdS to slow down the photocorrosion distinctly, delivering efficient H2 production with high selectivity. Our study will inspire exploration of various efficient non-noble-metal catalysts for practical H2 production from bio-based formic acid.

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments.

To realize PDE4 inhibitors with good developmental potentiality for the treatment of dementia, structure-based optimizations of lead compound FCPR03 resulted in novel aminophenylketones 9c and 9H with low nanomolar potency, which displayed comparable activity to rolipram, satisfactory bioavailability (F% = 36.92 and 42.96% respectively), and good blood-brain barrier (BBB) permeability switching from the cyclopropyl methoxy group to the cyclopropyl methylamine and the amide group to the corresponding ketone. Emetogenicity evaluation on a combined ketamine/xylazine anesthesia mice alternative model demonstrated that 9H displays no emetogenicity even at an oral dose of 5 mg/kg. In contrast, rolipram and roflumilast displayed emetogenicity at an oral dose of 0.5 mg/kg. In acute toxicological evaluation, 9H showed no obvious toxicological effect on mice when administered at oral doses below 625 mg/kg. Further investigations revealed that 9H improves the memory and cognitive impairment of Alzheimer's disease (AD) model mice induced by Aß25-35.

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease.

Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 µM) and PDE4D (IC50 = 1.88 µM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent anti-neuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.

[Spatiotemporal Differentiation and Degradation Analysis of Polybrominated Diphenyl Ethers in Sediments of Shanmei Reservoir and Its Inflowing River, Quanzhou, China].

To investigate the spatiotemporal differentiation of polybrominated diphenyl ethers (PBDEs) in urban water-source reservoirs and degradation sources of BDE homologues and their contributions, we analyzed the contents, pollution degrees, spatial distributions, hydrological period changes, inventories, profiles, and degradation source contributions of PBDEs in the surface sediments of Shanmei Reservoir and its inflowing river, Quanzhou, China. The results showed that the median ∑PBDEs (1072.1 ng ·g-1) in the inflowing river sediment was 6.7 times than that of the reservoir (160.4 ng ·g-1) and the total amount of ∑PBDEs in sediments per unit area (80.3 kg ·km-2) was 6.3 times than that of Taihu Lake and 188 times than that of the Great Lakes in North America. The pollution degrees of PBDEs in Shanmei Reservoir were more severe than those of most lakes and reservoirs at home and abroad, which was dominated by BDE-209 (84.5%-99.2%). Most of the sampling sites in the reservoir (r 0.564-0.994, P<0.034) and the inflowing river (r 0.953-1.0, P<0.000) had high similarity in the composition of PBDEs. Significantly positive correlations (r 0.779-0.964, P<0.005) were observed between the reservoir entry area and river sampling sites, which were stronger than the other functional areas, indicating that the inflowing river was a major pollution source of PBDEs in the Shanmei Reservoir. The tail region of the reservoir had low correlations with the inflowing river (r 0.454-0.915, P≤0.128), and was relatively much more affected by Jiudu Town. The changes in hydrological period of the ∑PBDEs were relatively consistent at each sampling site (r 0.617-0.714, P≤0.077), but the impact of the changes in the hydrological period on the ∑PBDEs was not statistically significant (P=0.178, Two-Way ANOVA). However, the site changes had a significant influence on the ∑PBDEs (P=0.0001), and significant or nearly differences were observed between the reservoir entry area and other functional areas (P 0.019-0.061), indicating that the spatial distribution variations of the PBDEs in reservoir sediments were greater than the changes in hydrological period. The natural degradation of the PBDEs gradually increased from the river to the reservoir entry area and then to the central reservoir area. The reductive debromination rates varied at different brominated levels, and some BDE homologues accumulated due to their slowly continued degradation velocities. Research on abundance ratios indicated that the lower brominated BDE homologues were mainly derived from the natural degradation of decabromodiphenyl ether by stepwise reductive debromination. Approximately 70% of Nona-BDE produced by Deca-BDE degradation could rapidly be degraded to form Octa-BDE. Approximately 85% of BDE-208 was derived from the degradation of BDE-209. During the degradation process from Octa-BDE to Penta-BDE, some Octa-BDE and Hexa-BDE homologues accumulated due to relatively slower degradation velocities, and the degradation rates of Penta-BDE to Tri-BDE were above 70%.

Synthesis of 4-Oxoisoxazoline N-Oxides via Pd-Catalyzed Cyclization of Propargylic Alcohols with tert-Butyl Nitrite.

A cyclization of propargylic alcohols with tert-butyl nitrite at room temperature in air was achieved using Pd(OAc)2 as catalyst. The first reported 4-oxoisoxazoline N-oxides could be directly accessed from a range of multisubstituted propargylic alcohols in moderate to excellent yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladium-catalyzed NO2 addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.

Eosin Y- and Copper-Catalyzed Dark Reaction To Construct Ene-γ-Lactams.

Eosin Y, a common organo-photocatalyst in visible-light photoredox processes, was found to show excellent catalytic activities for thermal redox reactions under a catalytic amount of Cu(OAc)2. With this catalytic system, vinyl azides and ketene silyl acetals combine to form formal [3 + 2] cycloadducts by α-ester radical addition without light irradiation. This method provides a mild and straightforward paradigm to prepare important synthons of five-membered ene-γ-lactams and bridge ring lactams. It is the first example of an eosin Y-catalyzed redox reaction in the dark.