Coerulein B: a water-soluble and water-compatible near-infrared photoredox catalyst.

The recent expansion of photoredox catalysis into chemical biology has underscored the importance of photochemistry, attracting the attention of many researchers. On the other hand, as conventional photoredox catalysts were developed for organic synthesis, there is a necessity to develop biocompatible photoredox catalysts. Here, we show a water-soluble and water-compatible near-infrared (NIR) photoredox catalyst, coerulein B (CB). CB is a water-soluble molecule with a slightly twisted molecular structure, and its anionic species (CB-) exhibits NIR absorption and emission. We demonstrated that CB works as a water-compatible photoredox catalyst in the coupling reaction of pyridine hydrochloride and aryldiazonium salt. These results indicate that CB is one of the promising candidates for photocatalysts used in biological reactions.

One-Pot Synthesis of Pentasubstituted Pyridines following the Gold(I)-Catalyzed Aza-Enyne Metathesis/6π-Electrocyclization-Aromatization Sequence.

The one-pot de novo synthesis of pentasubstituted pyridines was realized following the process of Au(I)-autotandem catalysis and subsequent aromatization. The process involves aza-enyne metathesis with aryl propiolates to yield 1-azabutadienes and their addition/6π-electrocyclization sequence with the other propiolate units. The resultant 1,4-dihydropyridines were aromatized to furnish the pyridines in the presence of atmospheric oxygen. The aryl propiolates were regioselectively incorporated into the ring system to afford 2-arylpyridines as the sole product.

Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory activity.

Tuning the electrophilicities of Michael acceptors is important for the development of targeted covalent drugs. To this end, the electronic effects of electrophilic structures have been well investigated, but not the steric effects. In this work, we synthesized ten α-methylene cyclopentanones (MCPs), screened them for NF-κB inhibitory activity, and analyzed their conformations. We found that MCP-4b, MCP-5b, and MCP-6b are novel NF-κB inhibitors, whereas the corresponding diastereomers MCP-4a, MCP-5a, and MCP-6a are inactive. Conformational analysis suggested that the stereochemistry of the side chain (R) on MCPs dictates the stable conformation of the core bicyclic 5/6 ring system. The conformational preference seemed to influence their reactivity toward nucleophiles. Consequently, a thiol reactivity assay showed that MCP-5b has higher reactivity than MCP-5a. The results indicate that the conformational switching of MCPs may control reactivity and bioactivity in the presence of steric effects.

Structure-activity relationship and mechanistic study on guggulsterone derivatives; Discovery of new anti-pancreatic cancer candidate.

Pancreatic cancer is one of the deadliest types of malignancies. A new intervention aiming to combat pancreatic cancer is targeting its extra-ordinary ability to tolerate nutrition starvation, a phenomenon known as "Austerity". As a part of a research program aiming to develop a new-generation of anticancer agents, known as "anti-austerity agents", guggulsterone derivatives (GSDs) were identified as unique anti-austerity agents in terms of potency and selectivity. These agents are able to exert preferential cytotoxic activity only under nutrient-deprived conditions with little or no toxicity under normal conditions. In the present study, a library of 14 GSDs was synthesized and screened against PANC-1 human pancreatic cells. Among tested compounds, GSD-11 showed the most potent activity with PC50 a value of 0.72 µM. It also inhibited pancreatic cancer cell migration and colony formation in a concentration-dependent manner. A mechanistic study revealed that this compound can inhibit the activation of the Akt/mTOR signaling pathway. Therefore, GSD-11 could be a promising lead compound for the anticancer drug discovery against pancreatic cancer.

Inhibition of gastric H+,K+-ATPase by new dihydropyrazole derivative KYY-008.

The gastric proton pump (H+,K+-ATPase) responsible for the H+ secretion of gastric acid is an essential therapeutic target for acid-related diseases. H+,K+-ATPase belongs to a P2-type ATPase family. Here, we examined the effects of a newly synthesized dihydropyrazole derivative KYY-008 on the H+,K+-ATPase. KYY-008 concentration-dependently inhibited the enzyme activity of the ATPase in the membrane fractions prepared from isolated hog gastric mucosa and from human kidney HEK293 cells in which gastric H+,K+-ATPase is exogenously expressed. The IC50 values in these samples were 3.4 µM and 3.7 µM, respectively. In addition, KYY-008 significantly inhibited the H+,K+-ATPase-derived H+ uptake into the tightly sealed vesicles prepared from the hog gastric mucosa. In contrast, KYY-008 has no effect on the activities of other P2-type ATPases such as Na+,K+-ATPase and Ca2+-ATPase. KYY-008 did not change the ionic currents of voltage-dependent Ca2+ channels, that were potential targets for some dihydropyrazole derivatives. Together, we discovered a new dihydropyrazole derivative which acts as a selective inhibitor of gastric H+,K+-ATPase.

Divinylcarbinol Desymmetrization Strategy: A Concise and Reliable Approach to Chiral Hydroxylated Fatty Acid Derivatives.

By the aid of the catalytic desymmetrization of divinylcarbinol as one-pot asymmetric induction and protection of olefin, asymmetric total syntheses of two chiral hydroxylated fatty acid derivatives were successfully achieved. The desired stereoisomers could be concisely prepared in mild conditions in a highly convergent manner. Thus, this novel strategy can help stereochemical elucidations of natural products, which have difficulties in spectroscopic stereochemical analyses due to their local symmetries in the vicinities of the stereogenic secondary hydroxyl units.

Synthesis of guggulsterone derivatives as potential anti-austerity agents against PANC-1 human pancreatic cancer cells.

E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC50 value of 1.6 µM and 3.2 µM, respectively. The effect of GSD-1 and GSD-7 was further evaluated in a real time using live cell imaging. Both of these compounds altered PANC-1 cell morphology, leading to cell death at sub micromolar concentration range. GSD-1 and GSD-7 also inhibited PANC-1 cell colony formation in a concentration-dependent manner. GSD-1 and GSD-7 are lead structure for the anti-austerity drug development.

2,2'-Biphenol/B(OH)3 Catalyst System for Nazarov Cyclization.

A novel catalyst system-a combination of the readily available 2,2'-biphenol with the inexpensive, nontoxic, and eco-friendly B(OH)3-promoted the Nazarov cyclization of activated and inactivated divinyl ketones to afford the corresponding cyclopentenones up to 96% yield under, in a cis-selective manner. Compared with the conventional harsh conditions with hazardous reagents, user-friendly method was established with bench-stable and easy-to-handle reagents.

A novel method for determining peroxisomal fatty acid ß-oxidation.

The purpose of this study is to establish an assay method to screen for chemical compounds that stimulate peroxisomal fatty acid ß-oxidation activity in X-linked adrenoleukodystropy (X-ALD) fibroblasts. In this investigation, we used 12-(1-pyrene)dodecanoic acid (pyrene-C12:0), a fluorescent fatty acid analog, as a substrate for fatty acid ß-oxidation. When human skin fibroblasts were incubated with pyrene-C12:0, ß-oxidation products such as pyrene-C10:0 and pyrene-C8:0 were generated time-dependently. These ß-oxidation products were scarcely detected in the fibroblasts from patients with Zellweger syndrome, a peroxisomal biogenesis disorder. In contrast, in fibroblasts with mitochondrial carnitine-acylcarnitine translocase deficiency, the ß-oxidation products were detected at a level similar to control fibroblasts. These results indicate that the ß-oxidation of pyrene-C12:0 takes place in peroxisomes, but not mitochondria, so pyrene-C12:0 is useful for measuring peroxisomal fatty acid ß-oxidation activity. In X-ALD fibroblasts, the ß-oxidation activity for pyrene-C12:0 was approximately 40 % of control fibroblasts, which is consistent with previous results using [1-(14)C]lignoceric acid as the substrate. The present study provides a convenient procedure for screening chemical compounds that stimulate the peroxisomal fatty acid ß-oxidation in X-ALD fibroblasts.

A Macrosphelide as the Unexpected Product of a Pleurotus ostreatus Strain-Mediated Biotransformation of Halolactones Containing the gem-Dimethylcyclohexane Ring. Part 1.

The aim of the study was to obtain new compounds during biotransformation of two halocompounds, the δ-bromo and δ-iodo-γ-bicyclolactones 1 and 2. Unexpectedly Pleurotus ostreatus produced together with the hydroxylactone, 2-hydroxy-4,4-dimethyl-9-oxabicyclo[4.3.0]nonane-8-one (3), its own metabolite (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone (4). The method presented here, in which this macrosphelide 4 was obtained by biotransformation, has not been previously described in the literature. To the best of our knowledge, this compound has been prepared only by chemical synthesis to date. This is the first report on the possibility of the biosynthesis of this compound by the Pleurotus ostreatus strain. The conditions and factors, like temperature, salts, organic solvents, affecting the production of this macrosphelide by Pleurotus ostreatus strain were examined. The highest yield of macroshphelide production was noticed for halolactones, as well with iodide, bromide, iron and copper (2+) ions as inductors.

Highly Efficient Access to Both Geometric Isomers of Silyl Enol Ethers: Sequential 1,2-Brook/Wittig Reactions.

Novel sequential 1,2-Brook/Wittig reactions were developed for the preparation of silyl enol ethers. This method enables highly selective preparation of both geometric isomers of glyoxylate silyl enol ethers, using aldehydes (E-selective) and tosylimines (Z-selective) as a Wittig electrophile. The salt-free conditions of this reaction system are likely to be advantageous for switching the selectivity. The optimal reaction conditions and generality of the reaction were investigated, and plausible explanations for the observed selectivity were also discussed.

Synthesis of long-chain fatty acid derivatives as a novel anti-Alzheimer's agent.

In order to develop new drugs for Alzheimer's disease, we prepared 17 fatty acid derivatives with different chain lengths and different numbers and positions of double bonds by using Wittig reaction and stereospecific hydrogenation of triple bonds as key reactions. Among them, (4Z,15Z)-octadecadienoic acid (10) and (23Z,34Z)-heptatriacontadienoic acid (16) showed the most potent neurite outgrowth activities on Aß(25-35)-treated rat cortical neurons, which activities were comparable to that of a positive control, NGF. Both fatty acids 10 and 16 possess two (Z)-double bonds at the n-3 and n-14 positions, which might be important for the neurite outgrowth activity.

Nonpolar selective emission (NPSE) of carbonyl-bridged rhodols.

Polarity-responsive luminophores (PRLs), whose emission properties change in response to the polarity of the surrounding environment, are used for the fluorescence sensing of intracellular environments and various chemical compounds. Herein, we propose a concept called nonpolar selective emission (NPSE) for the development of a new PRL family. Unlike the conventional emission of PRLs, the NPSE luminophore can switch to a completely non-emissive state upon a slight increase in solvent polarity. The NPSE concept offers a new means of distinguishing between nonpolar and low-polarity environments. Moreover, the NPSE property is little affected by the viscosity of the surrounding medium. We demonstrate that NPSE dyes can be used as emission sensors for molecular gases. Furthermore, we discovered the potential use of NPSE dyes as a time-dependent security ink triggered by the volatilization of polar molecules.

Search for a novel SIRT1 activator: structural modification of SRT1720 and biological evaluation.

Syntheses and biological evaluation of novel SRT1720 derivatives are described in search for new candidates of SIRT1 activator. Several parts of the SRT1720 structure, including piperazine moiety, quinoxaline ring on the amide group, and position of the amide function, were modified, and the assay results indicated that transfer of the ortho amide-substituent regarding to the imidazo[1,2-b]thiazole core onto the meta position resulted in improvement of SIRT1 activation ability. Modeling analyses of SRT1720 and the most potent derivative bound to model complex of SIRT1 with peptide substrate were also performed.

Structure-activity-relationship studies on dihydrofuran-fused perhydrophenanthrenes as an anti-Alzheimer's disease agent.

As an extended study on development of anti-Alzheimer's disease agent, we newly synthesized various dihydrofuran-fused perhydrophenanthrenes via o-quinodimethane chemistry. This study revealed that the introduction of carbon side-chain on 8-position or removal of the acetal moiety on 3-position arose a cytotoxicity on rat cortical neurons. On the other hand, the ethereal or thio-ethereal substituent on 8-position enhanced the elongation effect on Aß-damaged neurons. The necessity of the cyano group on 10b position was also proved in this structure-activity-relationship study.

Synthesis and structure-activity relationship of 2-phenyliminochromene derivatives as inhibitors for aldo-keto reductase (AKR) 1B10.

Inhibitors of a human member (AKR1B10) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of cancer. Recently, we have discovered (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) as the potent competitive inhibitor using the virtual screening approach, and proposed its 4-methoxy group on the 2-phenylimino moiety as an essential structural prerequisite for the inhibition. In this study, 18 derivatives of 1 were synthesized and their inhibitory potency against AKR1B10 evaluated. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (5n) was the most potent inhibitor showing a Ki value of 1.3nM. The structure-activity relationship of the derivatives indicated that the 7-hydroxyl group on the chromene ring, but not the 4-methoxy group, was absolutely required for inhibitory activity, The molecular docking of 5n in AKR1B10 and site-directed mutagenesis of the enzyme residues suggested that the hydrogen-bond interactions between the 7-hydroxyl group of 5n and the catalytic residues (Tyr49 and His111) of the enzyme, together with a π-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition.

Synthesis and biological evaluation of N-(2-fluorophenyl)-2ß-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases.

In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2ß-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079µM respectively. It is noteworthy that our designed N-phenyl-2ß-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.

Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma.

BACKGROUND AND OBJECTIVE: In asthma, reduced histone deacetylase activity and enhanced histone acetyltransferase activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III histone deacetylase, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated. METHODS: The effect of SRT1720, a synthetic activator of Sirt1, in an ovalbumin (OVA)-induced asthma mouse model was investigated. The effect of SRT1720 and resveratrol on OVA stimulation in splenocytes from OVA-sensitized and challenged mice was also examined. RESULTS: In OVA-sensitized and challenged mice (OVA mice) compared with saline-sensitized and challenged mice (control mice), Sirt1 messenger RNA expression in the lungs was decreased (P = 0.02), while cellular infiltration, airway eosinophilia and bronchoalveolar lavage (BAL) fluid levels of interleukin (IL)-4, IL-5 and IL-13 were increased (P < 0.01). In OVA mice, SRT1720 treatment decreased total and eosinophil cell counts and IL-5 and IL-13 levels in the BAL fluid compared with the vehicle treatment (P < 0.05). In OVA mice, SRT1720 treatment also decreased inflammatory cell lung infiltrates histologically (P = 0.002). Both SRT1720 and resveratrol suppressed OVA-induced cell proliferation and IL-6 (P < 0.05) and tumour necrosis factor-α (TNF-α) (P < 0.05) production in splenocytes (P < 0.01). CONCLUSIONS: The Sirt1 activator SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA-induced mouse model of asthma. SRT1720 and resveratrol suppressed OVA-induced splenocyte proliferation and TNF-α and IL-6 production. Sirt1 activators might have beneficial effects in asthmatics by suppressing inflammation.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Synthesis of dihydrofuran-fused perhydrophenanthrenes having a phenolic hydroxyl group as a novel anti-Alzheimer's disease agent.

As a part of our research program on developing novel anti-Alzheimer's disease medicines, several dihydrofuran-fused perhydrophenanthrenes (DFs) possessing a phenolic hydroxyl group were found to exhibit potent dendritic and axonal regeneration activities. Introduction of a methoxy group into the perhydrophenanthrene skeleton was successfully achieved via a PhI(OAc)(2)-mediated phenolic oxidation of a benzocyclobutene nucleus and subsequent tandem intramolecular electrocyclic reactions based on o-quinodimethane chemistry. We could reveal that a new methoxy derivative having a phenolic hydroxyl group exerted the most significant effects on the dendritic and axonal extensions in the damaged neurons, among DFs examined in this study.