IL-6 Inhibitory Compounds from the Aerial Parts of and Their Anticancer Activities on Ovarian Cancer Cell Lines.

Buch-Ham, a perennial woody vine belonging to the Piperaceae family, is traditionally used in Southeast Asia for treating various ailments such as malaria, headache, and hepatitis. This study described the isolation and identification of three new compounds, piperamides I-III (-), which belong to the maleimide-type alkaloid skeletons, along with fifteen known compounds (-) from the methanol extract of the aerial parts of . Their chemical structures were elucidated using spectroscopic methods (UV, IR, ESI-Q-TOF-MS, and 1D/2D NMR).

Non-Palladium-Catalyzed Approach to the Synthesis of ()-3-(1,3-Diarylallylidene)Oxindoles.

Two novel synthetic approaches for synthesizing ()-3-(1,3-diarylallylidene)oxindoles from oxindole were developed. All previously reported methods for synthesizing 3-(1,3-diarylallylidene)oxindoles utilized palladium-catalyzed reactions as a key step to form this unique skeleton. Despite high efficiency, palladium-catalyzed reactions have limitations in terms of substrate scope.

Total Synthesis of Cyclopiamide A Using Palladium-Catalyzed Domino Cyclization.

Total synthesis of cyclopiamide A was accomplished using a palladium-catalyzed domino cyclization. Three rings in the tetracyclic skeleton of cyclopiamide A were constructed in a one-step domino reaction incorporating double carbopalladation and C-H activation.

Isolation of six anthraquinone diglucosides from cascara sagrada bark by high-performance countercurrent chromatography.

In this study, high-performance countercurrent chromatography was employed to isolate six anthraquinone diglucosides, namely, cascarosides A-F, from cascara sagrada (Rhamnus purshiana DC [Rhamnaceae]) bark. The n-butanol-soluble extract of cascara sagrada was separated by off-line two-dimensional high-performance countercurrent chromatography. The first-dimensional high-performance countercurrent chromatography resolved the n-butanol-soluble extract (510 mg) of cascara sagrada using the flow-rate gradient method with a chloroform-methanol-isopropanol-water (6:6:1:4, v/v/v/v, normal-phase mode) system to afford four anthraquinone diglucoside fractions (groups I [cascarosides C-D, 71 mg], II [cascarosides E-F, 56 mg], III [cascaroside A, 53 mg], and IV [cascaroside B, 31 mg]).

Thiazolidine-2,4-dione-based irreversible allosteric IKK-β kinase inhibitors: Optimization into in vivo active anti-inflammatory agents.

Selective kinase inhibitors development is a cumbersome task because of ATP binding sites similarities across kinases. On contrast, irreversible allosteric covalent inhibition offers opportunity to develop novel selective kinase inhibitors. Previously, we reported thiazolidine-2,4-dione lead compounds eliciting in vitro irreversible allosteric inhibition of IKK-β.

Optimization study towards more potent thiazolidine-2,4-dione IKK-β modulator: Synthesis, biological evaluation and in silico docking simulation.

Inhibition of IKK-β (inhibitor of nuclear factor kappa-B kinase subunit beta) has been broadly documentedas a promising approach for treatment of acute and chronic inflammatory diseases, cancer, and autoimmune diseases. Recently, we have identified a novel class of thiazolidine-2,4-diones as structurally novel modulators for IKK-β. Herein, we report a hit optimization study via analog synthesis strategy aiming to acquire more potent derivative(s), probe the structure activity relationship (SAR), and get reasonable explanations for the elicited IKK-β inhibitory activities though an in silico docking simulation study.

Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4-methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells.

We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKβ inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells.

Design, synthesis and biological evaluation of novel thiazolidinedione derivatives as irreversible allosteric IKK-β modulators.

The kinase known as IKK-β activates NF-κB signaling pathway leading to expression of several genes contributing to inflammation, immune response, and cell proliferation. Modulation of IKK-β kinase activity could be useful for treatment and management of such diseases. Starting from a discovered weakly active hit compound, twenty four thiazolidinedione-scaffold based chemical entities belonging to five series have been designed, synthesized and evaluated as potential IKK-β modulators.

Isolation and structural characterization of a novel sibutramine analogue, chlorosipentramine, in a slimming dietary supplement, by using HPLC-PDA, LC-Q-TOF/MS, FT-IR, and NMR.

A novel sibutramine analogue was detected in a slimming formula by high performance liquid chromatography with a photo diode detector array (HPLC-PDA). The unknown compound exhibited an ultraviolet (UV) spectrum that was similar to that of chlorosibutramine, despite having a different HPLC retention time. Further analysis of the slimming formula by LC-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) showed that the unknown compound had the formula CHClN.

Duodenal Niemann-Pick C1-like 1 expression was negatively correlated with liver X receptor expression in nonalcoholic fatty liver disease.

Background/aims: Intestinal cholesterol absorption includes intestinal Niemann-Pick C1-like 1 (NPC1L1) and is an important target pathway in nonalcoholic fatty liver disease (NAFLD). We investigated the expression of NPC1L1 and its correlation with liver X receptor (LXR) expression in peripheral mononuclear (PMN) cells in patients with NAFLD.

Methods: We evaluated intestinal expression of NPC1L1 in 25 NAFLD patients and 28 healthy controls.

Identification and structural elucidation of a new sildenafil analogue, dithiopropylcarbodenafil, from a premixed powder intended as a dietary supplement.

A new sildenafil analogue was detected during the monitoring of a premixed powder intended as a dietary supplement. The ultraviolet (UV) spectrum of the unknown compound was similar to that of dithiodesmethylcarbodenafil and dithiodesethylcarbodenafil, although their corresponding HPLC peaks were observed at different retention times. The chemical structure of the unknown compound was characterized by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS), followed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy.

Consecutive One-Pot versus Domino Multicomponent Approaches to 3-(Diarylmethylene)oxindoles.

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity.

Stereoselective Synthesis of 3-(1,3-Diarylallylidene)oxindoles via a Palladium-Catalyzed Tandem Reaction.

We have developed an efficient three-component tandem reaction for the synthesis of 3-(1,3-diarylallylidene)oxindoles combining three palladium-catalyzed reactions: the Sonogashira, Heck, and Suzuki-Miyaura reactions. This method allows a stereoselective approach to each (E)- and (Z)-isomer by ligand change and controlling the reaction temperature.

Aspirination of α-Aminoalcohol (Sarpogrelate M1).

Aspirination of α-aminoalcohol (sarpogrelate M1) has been performed under various general esterification conditions. In most cases, the desired aspirinate ester was obtained at a low yield with unexpected byproducts, the formation of which was mostly derived from the chemical properties of the tertiary α-amino group. After systematic analysis of those methods, the aspirinated sarpogrelate M1 was prepared using a two-step approach combining salicylate ester formation and acetylation.

Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease.

Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.

Identification and characterization of potent, selective and metabolically stable IKKβ inhibitor.

We have previously reported the identification of a rhodanine compound (1) with well-balanced inhibitory activity against IKKβ and collagen-induced TNFα activated cells. However, we need more optimized compounds because of its instability over plasma and microsome. As part of a program directed toward the optimization of IKKβ inhibitor, we modified a substituent of parent compound to a series of functional groups.

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver.

Liver X receptor (LXR) is a member of the nuclear receptor superfamily, and it regulates various biologic processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver diseases. In the present study, we evaluated the effects of three cinnamamide derivatives on ligand-induced LXRα activation and explored whether these derivatives could attenuate steatosis in mice.

Discovery of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor suitable for antistaphylococcal agent.

We report the discovery, synthesis, and biological activities of phenoxy-4-pyrone and phenoxy-4-pyridone derivatives as novel inhibitors of enoyl-acyl carrier protein reductase (FabI). Pyridone derivatives showed better activities than pyrone derivatives against FabI and Staphylococcus aureus strains, including methicillin-resistant Staphylococcus aureus (MRSA). Among the pyridone derivatives, compound 16l especially exhibited promising activities against the MRSA strain and good pharmacokinetic profiles.

Palladium-Catalyzed One-Pot Approach to 3-(Diarylmethylene)oxindoles from Propiolamidoaryl Triflate.

3-(Diarylmethylene)oxindoles have been synthesized from propiolamidoaryl triflate utilizing a palladium-catalyzed one-pot reaction consisting of three successive reactions: Sonogashira, Heck, and Suzuki-Miyaura. This method allows for the production of a complex skeleton of 3-(diarylmethylene)oxindole from propiolamidoaryl triflate using a commercially available aryl iodide and arylboronic acid in a simple and efficient way with moderate yield and stereoselectivity.

Induction of NQO1 and Neuroprotection by a Novel Compound KMS04014 in Parkinson's Disease Models.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Lines of evidence suggest that oxidative stress is a major factor contributing to the vulnerability of DA cells and that the enzyme NAD(P)H quinone oxidoreductase (NQO1) provides protection in these cells. In the present study, we report the synthesis of a novel compound KMS04014 and show that it induces NQO1 gene expression and protects DAergic neuronal cells in both cell culture and animal models of PD.

LXR-α antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver.

Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXRα in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXRα activation and its ability to attenuate fatty liver in mice.

Successful reduction of off-target hERG toxicity by structural modification of a T-type calcium channel blocker.

To obtain an optimized T-type calcium channel blocker with reduced off-target hERG toxicity, we modified the structure of the original compound by introducing a zwitterion and reducing the basicity of the nitrogen. Among the structurally modified compounds we designed, compounds 5 and 6, which incorporate amides in place of the original compound's amines, most appreciably alleviated hERG toxicity while maintaining T-type calcium channel blocking activity. Notably, the benzimidazole amide 5 selectively blocked T-type calcium channels without inhibiting hERG (hERG/T-type⩾220) and L-type channels (L-type/T-type=96), and exhibited an excellent pharmacokinetic profile in rats.

2-Phenylbenzofuran derivatives alleviate mitochondrial damage via the inhibition of β-amyloid aggregation.

To obtain modulators for reducing mitochondrial damage by the inhibition of Aβ oligomer formation, 2-phenylbenzofuran derivatives were designed and prepared. Their inhibitory activity against Aβ fibril formation was screened using ThT fluorescence assay, and the effect of derivatives on mitochondrial function was evaluated using JC-1 and MTT assay. 2-Phenylbenzofuran derivatives with dimethylamino group at p-position had an excellent inhibitory activity against Aβ fibril formation.

Glucuronidation of a sarpogrelate active metabolite is mediated by UDP-glucuronosyltransferases 1A4, 1A9, and 2B4.

Sarpogrelate is a selective serotonin 5-HT2A-receptor antagonist used to treat patients with peripheral arterial disease. This drug is rapidly hydrolyzed to its main metabolite (R,S)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol (M-1), which is mainly excreted as a glucuronide conjugate. Sarpogrelate was also directly glucuronidated to an O-acyl glucuronide and a N-glucuronide by UDP-glucuronosyltransferases (UGTs) in human liver microsomes (HLMs).