Identification of a novel inhibitor of liver cancer cell invasion and proliferation through regulation of Akt and Twist1.

When primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial-mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

Enhancing SSVEP-Based Brain-Computer Interface with Two-Step Task-Related Component Analysis.

Among various methods for frequency recognition of the steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) study, a task-related component analysis (TRCA), which extracts discriminative spatial filters for classifying electroencephalogram (EEG) signals, has gathered much interest. The TRCA-based SSVEP method yields lower computational cost and higher classification performance compared to existing SSVEP methods. In spite of its utility, the TRCA-based SSVEP method still suffers from the degradation of the frequency recognition rate in cases where EEG signals with a short length window are used. To address this issue, here, we propose an improved strategy for decoding SSVEPs, which is insensitive to a window length by carrying out two-step TRCA. The proposed method reuses the spatial filters corresponding to target frequencies generated by the TRCA. Followingly, the proposed method accentuates features for target frequencies by correlating individual template and test data. For the evaluation of the performance of the proposed method, we used a benchmark dataset with 35 subjects and confirmed significantly improved performance comparing with other existing SSVEP methods. These results imply the suitability as an efficient frequency recognition strategy for SSVEP-based BCI applications.

Efficient kinetic resolution in the asymmetric transfer hydrogenation of 3-aryl-indanones: applications to a short synthesis of (+)-indatraline and a formal synthesis of (R)-tolterodine.

Efficient kinetic resolution (KR) occurs in asymmetric transfer hydrogenation (ATH) reactions of racemic 3-aryl-1-indanones using commercial (R,R)- or (S,S)-Ts-DENEB as a catalyst, a 1 : 5 mixture of HCO2H and Et3N as a hydrogen source and MeOH as solvent. This process at room temperature produces near equal yields of cis-3-arylindanols with high dr and ee, and unreacted 3-arylindanones with excellent ee. Stereoselective transformations of 3-arylindanols and 3-arylindanones, generated by using the ATH-KR protocol, were carried out to form (+)-indatraline and synthetically valuable (R)-6-methyl-4-phenylcoumarine, which is a key intermediate in the preparation of (R)-tolterodine, (S)-4-aryl-3,4-dihydroquinoline-2(1H)-one and (S)-4-aryl-3,4-dihydroisoquinoline-1(2H)-one.

Stereoselective Synthesis of Highly Functionalized 5- and 6-Membered Aminocyclitols Starting with a Readily Available 2-Azetidinone.

Stereoselective transformations of 4-vinyl-2-azetidinone derivative 4 into a variety of highly functionalized 6- and 5-membered carbocyclic compounds 7 and 9 were carried out using sequences involving sequential C1-N bond cleavage and Ru-catalyzed ring-closing metathesis. The derived carbocycles were further transformed into polyhydroxylated 6- and 5-membered aminocyclitols.

DBU-Promoted Dynamic Kinetic Resolution in Rh-Catalyzed Asymmetric Transfer Hydrogenation of 5-Alkyl Cyclic Sulfamidate Imines: Stereoselective Synthesis of Functionalized 1,2-Amino Alcohols.

Dynamic kinetic resolution (DKR)-driven asymmetric transfer hydrogenation of 5-alkyl cyclic sulfamidate imine produces the corresponding sulfamidate with excellent levels of diastereo- and enantioselectivity by employing a HCO2H/DBU mixture as the hydrogen source in the presence of the Noyori-type chiral Rh-catalyst at room temperature for 1 h. In this process, DKR was induced by DBU-promoted rapid racemization of the substrate. Stereoselective transformations of the resulting cyclic sulfamidates to functionalized enantiomerically enriched 1,2-amino alcohol and chiral amine substances are also described.

Tandem Rh-Catalyzed Oxidative C-H Olefination and Cyclization of Enantiomerically Enriched Benzo-1,3-Sulfamidates: Stereoselective Synthesis of trans-1,3-Disubstituted Isoindolines.

A tandem process, involving Rh(III)-catalyzed oxidative C-H olefination of enantiomerically enriched 4-aryl-benzo-1,3-sulfamidates and subsequent intramolecular aza-Michael cyclization has been developed. The reaction produces trans-benzosulfamidate-fused-1,3-disubstituted isoindolines as major products, in which the configurational integrity of the stereogenic center in the starting material is preserved. Further transformations of the benzosulfamidate-fused-1,3-disubstituted isoindolines are described.

Stereoselective Synthesis of Functionalized 1,3-Disubstituted Isoindolines via Rh(III)-Catalyzed Tandem Oxidative Olefination-Cyclization of 4-Aryl-cyclic Sulfamidate-5-Carboxylates.

A new method for the direct, stereoselective synthesis of highly functionalized 1,3-disubstituted isoindolines 6 from enantiomerically enriched cyclic 4-aryl-sulfamidate-5-carboxylates (5) is described. The process involves sulfamidate directed, Rh(III)-catalyzed tandem ortho C-H olefination of the 4-aryl-sulfamidate-5-carboxylates and subsequent cyclization by aza-Michael addition. In the reaction, which generates trans-1,3-disubstituted isoindolines exclusively, the configurational integrity of the stereogenic center in the starting cyclic sulfamidate is completely retained in the product. Examples are provided which show that the cyclic sulfamidate moiety not only serves as a chiral directing group but also as a versatile handle for further functionalization of the generated isoindoline ring system.

Stereoselective synthesis of 1,3-disubstituted isoindolines via Rh(III)-catalyzed tandem oxidative olefination-cyclization of 4-aryl cyclic sulfamidates.

Rh(III)-catalyzed tandem ortho C-H olefination of cyclic 4-aryl sulfamidates (1) and subsequent intramolecular cyclization are described. This reaction serves as a method for the direct and stereoselective synthesis of 1,3-disubstituted isoindolines (3) starting with enantiomerically enriched 4-aryl cyclic sulfamidates. In this process, the configurational integrity of the stereogenic center in the starting cyclic sulfamidate is completely retained. In addition, the process generates trans-1,3-disubstituted isoindolines exclusively.

Stereoselective Synthesis of 4-Substituted Cyclic Sulfamidate-5-Phosphonates by Using Rh-Catalyzed, Asymmetric Transfer Hydrogenation with Accompanying Dynamic Kinetic Resolution.

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation of 4-substituted cyclic sulfamidate imine-5-phosphonates produces the corresponding cyclic sulfamidate-5-phosphonates. The process employs a HCO2H/Et3N mixture as the hydrogen source and the chiral Rh catalysts, (R,R)- or (S,S)-Cp*RhCl(TsDPEN), and it takes place at room temperature within 1 h with high yields and high levels of stereoselectivity.

Stereoselective synthesis of 4-substituted-cyclic sulfamidate-5-carboxylates by asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution and applications to concise stereoselective syntheses of (-)-epi-cytoxazone and the taxotere side-chain.

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation reactions of cyclic sulfamidate imine-5-carboxylate esters were developed. Applications of the new methodology to stereoselective syntheses of the taxotere side-chain and (-)-epi-cytoxazone are described.

Xanthene derivatives increase glucose utilization through activation of LKB1-dependent AMP-activated protein kinase.

5' AMP-activated protein kinase (AMPK) is a highly conserved serine-threonine kinase that regulates energy expenditure by activating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. Therefore AMPK activators are considered to be drug targets for treatment of metabolic diseases such as diabetes mellitus. To identify novel AMPK activators, we screened xanthene derivatives. We determined that the AMPK activators 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-nitro-phenyl)-thioureido]-ethyl}-amide (Xn) and 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-cyano-phenyl)-thioureido]-ethyl}-amide (Xc) elevated glucose uptake in L6 myotubes by stimulating translocation of glucose transporter type 4 (GLUT4). Treatment with the chemical AMPK inhibitor compound C and infection with dominant-negative AMPKa2-virus inhibited AMPK phosphorylation and glucose uptake in myotubes induced by either Xn or Xc. Of the two major upstream kinases of AMPK, we found that Xn and Xc showed LKB1 dependency by knockdown of STK11, an ortholog of human LKB1. Single intravenous administration of Xn and Xc to high-fat diet-induced diabetic mice stimulated AMPK phosphorylation of skeletal muscle and improved glucose tolerance. Taken together, these results suggest that Xn and Xc regulate glucose homeostasis through LKB1-dependent AMPK activation and that the compounds are potential candidate drugs for the treatment of type 2 diabetes mellitus.

Dynamic kinetic resolution based asymmetric transfer hydrogenation of α-alkoxy-ß-ketophosphonates. Diastereo- and enantioselective synthesis of monoprotected 1,2-dihydroxyphosphonates.

Dynamic kinetic resolution driven, asymmetric transfer hydrogenation reactions of a wide range of 2-substituted α-alkoxy-ß-ketophosphonates 3 were observed to proceed efficiently to give the corresponding 2-substituted α-alkoxy-ß-hydroxy phosphonates 4 with excellent levels of diastereo- and enantioselectivity. These processes are promoted by using well-defined, commercially available, chiral transition metal catalysts and a 0.2:1 mixture of formic acid and triethylamine as the hydrogen source and solvent.

Dynamic kinetic resolution-based asymmetric transfer hydrogenation of 2-benzoylmorpholinones and its use in concise stereoselective synthesis of all four stereoisomers of the antidepressant reboxetine.

Dynamic kinetic resolution-driven, asymmetric transfer hydrogenation reaction of 2-benzoylmorpholin-3-ones (4) proceeds efficiently to give the corresponding (2R,3S)- or (2S,3R)-2-(hydroxyphenylmethyl)morpholin-3-ones (6) with an excellent level of diastereo- and enantioselectivity and simultaneous control of two contiguous stereogenic centers in a single step. This process is employed to prepare all four stereoisomers of the antidepressant reboxetine.

Stereoselective synthesis of norephedrine and norpseudoephedrine by using asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution.

Each of the enantiomers of both norephedrine and norpseudoephedrine were stereoselectively prepared from the common, prochiral cyclic sulfamidate imine of racemic 1-hydroxy-1-phenyl-propan-2-one by employing asymmetric transfer hydrogenation (ATH) catalyzed by the well-defined chiral Rh-complexes, (S,S)- or (R,R)-Cp*RhCl(TsDPEN), and HCO(2)H/Et(3)N as the hydrogen source. The ATH processes are carried out under mild conditions (rt, 15 min) and are accompanied by dynamic kinetic resolution.

Identification of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as inhibitors of the phosphatase SerB653 in Porphyromonas gingivalis, implicated in periodontitis.

The serine phosphatase SerB653 plays a crucial role in the infection of Porphyromonas gingivalis, which contributes to the pathogenesis of periodontitis, an inflammatory disease of teeth-supporting tissues. Because functional loss of SerB653 eliminates the virulence of P. gingivalis, SerB653 inhibitors are considered potential periodontitis therapeutic or preventive agents. To identify SerB653 inhibitors with potent anti-periodontitis activity, we conducted a high-throughput screen of a representative 6800-compound subset of a synthetic chemical library of the Korea Chemical Bank (KCB) for compounds with activity against SerB653. The primary screening yielded 150 hits, and subsequent confirmatory studies identified eight compounds, mainly within a single cluster of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives, that showed greater than 50% inhibition of SerB653 activity at a concentration of 50µM. A second screening with a focused library identified 10 compounds with IC(50) values less than 10µM. In antibacterial tests, three of these compounds showed a minimum inhibitory concentration against P. gingivalis growth of 5-50nM.

Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation.

The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate imines was achieved via asymmetric transfer hydrogenation using a HCO(2)H/Et(3)N mixture as the hydrogen source and chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affording the corresponding cyclic sulfamidates in good yields with up to >20 : 1 dr and up to >99% ee.

A newly identified CG301269 improves lipid and glucose metabolism without body weight gain through activation of peroxisome proliferator-activated receptor alpha and gamma.

OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS: Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS: CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS: We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.

Enantioselective synthesis of cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation.

Asymmetric transfer hydrogenation (ATH) of cyclic sulfamidate imines 4 and 9, using a HCO(2)H/Et(3)N mixture as the hydrogen source and well-defined chiral Rh catalysts (S,S)- or (R,R)-2, Cp*RhCl(TsDPEN), effectively produces the corresponding cyclic sulfamidates with excellent yields and enantioselectivities at room temperature within 0.5 h. ATH of 4,5-disubstituted imines 9, having preexisting stereogenic centers, is shown to take place with dynamic kinetic resolution.

Anthelmintic activity of KSI-4088 against Caenorhabditis elegans.

Anthelmintic resistance is a serious global problem because of the worldwide spread of resistant nematodes in animals and humans. This has triggered increasing investment in research for new anthelmintics. Over the past decade, Caenorhabditis elegans has become a popular model organism for parasitic nematode research, and many examples have been published to illustrate its use. In this study, we investigated the effect of KSI-4088 on the egg hatching, larval development, and migration of the nematode worm C. elegans compared with ivermectin and levamisole (well-known anthelmintic drugs). KSI-4088 demonstrated anthelmintic activity on all assays of C. elegans. The anthelmintic activity of KSI-4088 on egg hatching and larval development showed especially strong activity, but assays showed that ivermectin and levamisole had no effects on C. elegans. In addition, KSI-4088 was capable of producing a change in the timing of the development of the worms at the L1-L3 and L4 stage. Also, we demonstrate that C. elegans L3-4 are more sensitive than adults to KSI-4088 in assay of migration. Our results indicate that KSI-4088 is an active anthelmintic compound that should be further investigated with the aim of developing a potent drug against nematodes.

Highly efficient, enantioselective syntheses of (S)-(+)- and (R)-(-)-dapoxetine starting with 3-phenyl-1-propanol.

A highly efficient, enantioselective sequence has been developed for the synthesis of (S)- and (R)-dapoxetine. The pathways involve the intermediacy of the 6-membered-ring sulfamate esters 4, which were generated by Du Bois asymmetric C-H amination reactions of the prochiral sulfamate 3, catalyzed by the chiral dirhodium(II) complexes. During the course of our research, the absolute configuration of the enantiomer of 4-pheny[1,2,3]oxathiazinane 2,2-dioxide (4r), prepared by the Du Bois asymmetric C-H amination reaction of 3 and the Rh(2)(S-nap)(4) catalyst, is determined to be R and not S as was originally reported.