Copper-Catalyzed Cycloaddition/Coupling Cascades of Azomethine Imines with Alkynes for Divergent Synthesis of ()-Alkenyl and Alkynyl ,-Bicyclic Pyrazolidinones.

Copper-catalyzed cycloaddition/coupling cascades utilizing azomethine imines and alkynes have been developed for the divergent synthesis of ()-alkenyl and alkynyl ,-bicyclic pyrazolidinones by varying the reaction conditions. The choice of inert or oxidative atmosphere plays a crucial role in determining the transformation pathways. These reactions have broad substrate scopes and mild conditions, making them potentially useful.

-Indole-Substituted Imidazolylidene Pd-PEPPSI Precatalysts: Enhanced Performance with a 3,5-Diisopropyl-4-indolyl Moiety.

Pd-PEPPSI complexes of -(4-indolyl)-'-phenylimidazol-2-ylidene (IIn) ligands with a 5-isopropyl-4-indolyl moiety are synthesized and evaluated in heteroarene C-H arylation, Suzuki-Miyaura cross-coupling, and Buchwald-Hartwig amination reactions. The IIn-Pd complex bearing a 3,5-diisopropyl-4-indolyl substituent () exhibits the best catalytic activity in this series and substantially outperforms commercial precatalyst PEPPSI-Pd-IPr. The results also suggest that the alkyl group at position 3 of the 4-indolyl moiety shows stronger impacts than that at position 5.

Isolation, synthesis and absolute configuration of 4,5-dihydroxypiperines improving behavioral disorder in AlCl-induced dementia.

A pair of stereoisomers of new 4,5-dihydroxypiperine was isolated from P. retrofractum and showed profound activity on AlCl-induced dementia. In order to determine their absolute configurations and biological activities, all four possible stereoisomers of 4,5-dihydroxypiperine were synthesized from piperidine by Sharpless asymmetric dihydroxylation and Mitsunobu reaction.

Caspase-8 knockdown suppresses apoptosis, while induces autophagy and chemo-sensitivity in non-small cell lung cancer cells.

Purpose: Drug resistance remains a major cause of relapse and therapeutic failure in non-small cell lung cancer (NSCLC). The purpose of this investigation is to explore the relationship between caspase-8 level and chemo-sensitivity, as well as its underlying mechanism in NSCLC cells.

Methods: NSCLC cell line, A549 cells was used to investigate the influence of caspase-8 on the biological behavior .

Synthesis of Amino Acids by Base-Enhanced Photoredox Decarboxylative Alkylation of Aldimines.

A photoredox decarboxylative coupling of -hydroxyphthalimide esters with aldimines is reported for synthesizing α-amino esters. A broad scope of alkyl radicals generated under visible light irradiation adds to glyoxylate aldimines in reliably good to excellent yields. Adding inorganic bases such as potassium carbonate significantly enhanced the yields by suppressing the umpolung side reaction.

Homology modeling and 3D-QSAR study of benzhydrylpiperazine δ opioid receptor agonists.

The binding affinity of a series of benzhydrylpiperazine δ opioid receptor agonists were pooled and evaluated by using 3D-QSAR and homology modeling/molecular docking methods. Ligand-based CoMFA and CoMSIA 3D-QSAR analyses with 46 compounds were performed on benzhydrylpiperazine analogues by taking the most active compound BW373U86 as the template. The models were generated successfully with q value of 0.

Iron(II)-Catalyzed Radical Addition to Aldimines with Hantzsch Ester as a Two-Hydrogen Atom Donor.

The first Fe(OTf)-catalyzed radical addition to aldimines with Hantzsch ester as a two-hydrogen atom donor is reported. The tin-free reaction works well for electron-deficient substrates and provides a potentially useful approach to α-branched amines and α-amino acids.

Access to Multisubstituted 2(5 H)-Furanones Using Hydrogen Bonding-Promoted Ring-Closing Metathesis and Polyamine Workup.

Structurally complex 2(5 H)-furanones are potentially challenging targets for ring-closing metathesis (RCM). A hydrogen bonding-guided RCM strategy was developed in this study to provide 3-substituted and 3,4-disubstituted 2(5 H)-furanones in moderate to high yields with broad functional group tolerance. A workup procedure using ethylenediamine-derived polyamines such as tetraethylenepentylamine was also established to effectively remove Ru residues in products.

Copper-Catalyzed Decarboxylative Disulfonylation of Alkynyl Carboxylic Acids with Sulfinic Acids.

A copper-catalyzed decarboxylative disulfonylation of alkynyl carboxylic acids with sulfinic acids in aqueous solution has been developed. The reaction provides a straightforward and practical access to (E)-1,2-disulfonylethenes, which are important building blocks in synthetic organic chemistry, and exhibits a good functional group tolerance and excellent stereoselectivity. A possible mechanism for the transformation is proposed.

The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study.

Cognitive dysfunction in adult patients with neuromyelitis optica: a systematic review and meta-analysis.

The objective of this study was to investigate cognitive dysfunction in 24-60-year-old neuromyelitis optica (NMO) patients, demographically matched healthy subjects, and MS patients. We conducted a comprehensive literature review of the PubMed, Medline, EMBASE, CNKI, Wan Fang Date, Web of Science, and Cochrane Library databases from inception to May 2016 for case-control studies that reported cognitive test scores in NMO patients, healthy subjects, and MS patients. Outcome measures were cognitive function evaluations, including performance on attention, language, memory, information processing speed, and executive function tests.

Hydrogen bonding-promoted efficient Ru-catalyzed ring-closing metathesis of demanding homoallyl 2-(hydroxymethyl)acrylates.

An efficient hydrogen bonding-guided ring-closing metathesis (RCM) reaction of sterically demanding homoallyl 2-(hydroxymethyl)acrylates catalyzed by the Hoveyda-Grubbs 2nd generation catalyst was developed and the reaction mechanism was explored. Adding a substituent to the hydroxymethyl group in this scaffold resulted in a class of challenging RCM substrates, although usable yields could be obtained. However, substrates bearing a 1-oxygenated alkyl group on the homoallylic carbon gave excellent RCM yields, providing a practical solution.

Correction: Insights into the unexpected chemoselectivity in Brønsted acid catalyzed cyclization of isatins with enaminones: convenient synthesis of pyrrolo[3,4-c]quinolin-1-ones and spirooxindoles.

Correction for 'Insights into the unexpected chemoselectivity in Brønsted acid catalyzed cyclization of isatins with enaminones: convenient synthesis of pyrrolo[3,4-c]quinolin-1-ones and spirooxindoles' by Hui Xu et al., Chem. Commun.

Insights into the unexpected chemoselectivity in Brønsted acid catalyzed cyclization of isatins with enaminones: convenient synthesis of pyrrolo[3,4-c]quinolin-1-ones and spirooxindoles.

Divergent cascade syntheses constitute a highly attractive and challenging area in synthetic chemistry, and can exhibit unexpected chemoselectivity. Herein, a Brønsted acid-controlled protocol is described for the efficient catalysis of two different reactions, namely acylation cascade- and [1+2+3]-type cyclization of enaminones and isatins for the concise synthesis of highly functionalized pyrrolo[3,4-c]quinolin-1-ones and spirooxindoles in the presence of carboxylic acids and KHSO4, respectively. The observed chemoselectivity was reasonably explained by trapping the intermediate α,β-unsaturated 2-oxindoles, and the source of the hydroxyl group, carbocation intermediate, and amination reaction were also evaluated.

Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs.

The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs.

Oxidative Radical Addition/Cyclization Cascade for the Construction of Carbonyl-Containing Quinoline-2,4(1H,3H)-Diones.

Oxidative radical addition/cyclization cascade of o-cyanoarylacrylamides with α-keto acids as well as aldehydes is reported. This transformation exhibits a wide substrate scope and significant functional group tolerance and provides a convenient and highly efficient access to carbonyl-containing quinoline-2,4(1H,3H)-diones. A possible mechanism for the transformation is proposed.

Copper-catalyzed cascade addition/cyclization: highly efficient access to phosphonylated quinoline-2,4(1H,3H)-diones.

A novel and facile Cu-catalyzed addition/cyclization cascade of o-cyanoarylacrylamide was developed. The process exhibits significant functional group tolerance, and provides an efficient and straightforward pathway for the synthesis of various phosphonylated quinoline-2,4(1H,3H)-diones.

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion.

Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca(2+) mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0.

In Vitro Activity of Geldanamycin Derivatives against Schistosoma japonicum and Brugia malayi.

Geldanamycin (GA) is a benzoquinone-containing ansamycin that inhibits heat shock protein 90. GA derivatives are being evaluated as anti-neoplastic agents, but their utility against parasites whose heat shock proteins (Hsps) have homology with human Hsp90 is unknown. The activities of four synthetic GA derivatives were tested in vitro using adult Brugia malayi and Schistosoma japonicum.

Geldanamycin derivative inhibition of HGF/SF-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation.

Ansamycins, including geldanamycin and the derivative 17-allylamino-17-demethoxygeldanamycin, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90.

Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion.

Induction of the urokinase-type plasminogen activator (uPA) by hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in tumor cell invasion and metastasis that is mediated through the Met receptor tyrosine kinase. Geldanamycins (GA) are antitumor drugs that bind and inhibit HSP90 chaperone activity at nanomolar concentrations (nM-GAi) by preventing proper folding and functioning of certain oncoproteins. Previously, we have shown that a subset of GA derivatives exhibit exquisite potency, inhibiting HGF/SF-induced uPA-plasmin activation at femtomolar concentrations (fM-GAi) in canine MDCK cells.

Comparison of electrophilic amination reagents for N-amination of 2-oxazolidinones and application to synthesis of chiral hydrazones.

Comparison of several hydroxylamine-based electrophilic ammonia equivalents in the N-amination of 2-oxazolidinones revealed that O-(p-nitrobenzoyl)hydroxylamine (NbzONH(2)) and sodium hydride in dioxane is a superior reagent combination for this purpose. Practical preparations of a variety of chiral N-acylhydrazones by this method gave yields ranging from 45 to 95%. Methods for exchange or removal of the aldehyde component have been developed, making this a general route to chiral N-acylhydrazones of interest for asymmetric synthesis applications.