Linkage-Editing Pseudo-Glycans: A Reductive α-Fluorovinyl-C-Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities.

The acetal (O-glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore C-glycosides are of interest as more stable analogs. We hypothesized that, if the O-glycoside linkage plays a vital role in glycan function, the biological activities of C-glycoside analogs would vary depending on their substituents. Based on this idea, we adopted a "linkage-editing strategy" for the creation of glycan analogs (pseudo-glycans). We designed three types of pseudo-glycans with CH2 and CHF linkages, which resemble the O-glycoside linkage in terms of bond lengths, angles, and bulkiness, and synthesized them efficiently by means of fluorovinyl C-glycosylation and selective hydrogenation reactions. Application of this strategy to isomaltose (IM), an inducer of amylase expression, and α-GalCer, which activates iNKT cells, resulted in the discovery of CH2-IM, which shows increased amylase production ability, and CHF-α-GalCer, which shows activity opposite that of native α-GalCer, serving as an antagonist of iNKT cells.

2,5-Dimethyl-celecoxib induces early termination of inflammatory responses by transient macrophage accumulation and inhibits the progression of cardiac remodeling in a mouse model of cryoinjury-induced myocardial infarction.

In our previous study, we reported that 2, 5-dimethyl-celecoxib (DM-C), a derivative of celecoxib, prevents cardiac remodeling in different mouse models of heart failure, including myocardial infarction (MI). The inflammatory response after MI affects the progression of cardiac remodeling, wherein the immune cells, mainly macrophages, play crucial roles. Therefore, we evaluated the effect of DM-C on macrophages in a cryoinjury-induced myocardial infarction (CMI) mouse model. We observed that DM-C attenuated the deterioration of left ventricular ejection fraction and cardiac fibrosis 14 d after CMI. Gene expression of pro-inflammatory cytokines at the infarct site was reduced by DM-C treatment. Analysis of macrophage surface antigens revealed that DM-C induced transient accumulation of macrophages at the infarct site without affecting their polarization. In vitro experiments using peritoneal monocytes/macrophages revealed that DM-C did not directly increase the phagocytic ability of the macrophages but increased their number, thereby upregulating the clearance capacity. Moreover, DM-C rapidly excluded the cells expressing necrotic cell marker from the infarct site. These results suggested that DM-C enhanced the clearance capacity of macrophages by transiently increasing their number at the infarct site, and terminated the escape from the inflammatory phase earlier, thereby suppressing excessive cardiac remodeling and ameliorating cardiac dysfunction.

Differentiation-inducing factor 1 activates cofilin through pyridoxal phosphatase and AMP-activated protein kinase, resulting in mitochondrial fission.

Differentiation-inducing factor 1 (DIF-1) is a morphogen produced by Dictyostelium discoideum that inhibits the proliferation and migration of both D. discoideum and most mammalian cells. Herein, we assessed the effect of DIF-1 on mitochondria, because DIF-3, which is similar to DIF-1, reportedly localizes in the mitochondria when added exogenously, however the significance of this localization remains unclear. Cofilin is an actin depolymerization factor that is activated by dephosphorylation at Ser-3. By regulating the actin cytoskeleton, cofilin induces mitochondrial fission, the first step in mitophagy. Here, we report that DIF-1 activates cofilin and induces mitochondrial fission and mitophagy mainly using human umbilical vein endothelial cells (HUVECs). AMP-activated kinase (AMPK), a downstream molecule of DIF-1 signaling, is required for cofilin activation. Pyridoxal phosphatase (PDXP)-known to directly dephosphorylate cofilin-is also required for the effect of DIF-1 on cofilin, indicating that DIF-1 activates cofilin through AMPK and PDXP. Cofilin knockdown inhibits mitochondrial fission and decreases mitofusin 2 (Mfn2) protein levels, a hallmark of mitophagy. Taken together, these results indicate that cofilin is required for DIF-1- induced mitochondrial fission and mitophagy.

Flexible Alkylene Bridges as a Tool To Engineer Crystal Distyrylbenzene Structures Enabling Highly Fluorescent Monomeric Emission.

To design ultrabright fluorescent solid dyes, a crystal engineering strategy that enables monomeric emission by blocking intermolecular electronic interactions is required. We introduced propylene moieties to distyrylbenzene (DSB) as bridges between the phenyl rings either side of its C=C bonds. The bridged DSB derivatives formed compact crystals that emit colors similar to those of the same molecules in dilute solution, with high quantum yields. The introduction of flexible seven-membered rings to the DSB core produced moderate distortion and steric hindrance in the DSB π-plane. However, owing to this strategy, it was possible to control the molecular arrangement with almost no decrease in the crystal density, and intermolecular electronic interactions were suppressed. The bridged DSB crystal structure differs from other DSB derivative structures; thus, bridging affords access to novel crystalline systems. This design strategy has important implications in many fields and is more effective than the conventional photofunctional molecular crystal design strategies.

Oxidation of an Internal-Edge-Substituted [5]Helicene-Derived Phosphine Synchronously Enhances Circularly Polarized Luminescence.

Small chiral organic molecules with CD properties are in high demanded due to their potential use in promising electronic and biological applications. Herein, we reveal a system in which the oxidation of a phosphino group to the corresponding phosphine oxide on the inner rim of a helicene derivative induces a CPL response. Laterally π-extended 7,8-dihydro[5]helicenes bearing phosphine and phosphine oxide groups on their inner helical rims (i. e., the C1 position) were synthesized, and their helical structures were unambiguously determined by X-ray crystallography. The photophysical (UV/visible and emission) and chiroptical properties of these compounds were investigated in various solvents. Despite their structural similarities, phosphine oxide showed a significantly better CPL response than phosphine, with a high dissymmetry factor for emission (|glum |=(1.3-1.9)×10-3 ) that can be attributed to structural changes in the interior of the helicene helix.

Oxidation of an Internal-Edge-Substituted [5]Helicene-Derived Phosphine Synchronously Enhances Circularly Polarized Luminescence.

Invited for the cover of this issue are the groups of Kazuteru Usui and Satoru Karasawa at Showa Pharmaceutical University, and Yoshitane Imai at Kindai University. The image depicts how a phosphine-oxide-bearing helicene exhibits markedly enhanced CPL response in the excited state compared with that of one with a corresponding phosphine. Read the full text of the article at 10.1002/chem.202202922.

Stereochemical study on planar-chiral cyclic molecules using polysaccharide-based column chromatography.

The presence of planar chirality of a variety of medium-sized heterocycles, along with nine-membered cyclic ketone and its enol ester, was revealed by observation of isolable enantiomers by analytical high-performance liquid chromatography (HPLC) using a chiral stationary phase with a polysaccharide-based chiral selector. Several tens of milligrams of enantiomers of the planar-chiral molecules were successfully separated by preparative-scale HPLC, leading to the preparation of an enantioenriched sample. This in turn enabled detailed stereochemical studies, including measurement of half-lives of the optical activity and X-ray crystallography for elucidation of stereochemistry.

Analysis of Stereochemical Stability of Dynamic Chiral Molecules Using an Automated Microflow Measurement System.

An automated microflow measurement system for the kinetic study of racemization of dynamic chiral molecules was developed. This system facilitated the analysis of fast racemization within several seconds at elevated temperatures owing to its rapid heating ability, high performance for controlling short residence times, and ease of connection to HPLC systems for direct measurement of the enantiomeric purity. A more precise analysis was realized by combination of microflow and common batch measurements over a broad range of temperatures.

Preparation of Oxysterols by C-H Oxidation of Dibromocholestane with Ru(Bpga) Catalyst.

Seven mono- and dihydroxycholesterols were prepared by direct C-H oxidation of the cholestane skeleton with a recently developed Ru(Bpga) catalyst (Ru(Bpga) = [RuCl (bpga) (PPh3)] Cl; bpga = 2-(bis(pyridin-2-ylmethyl)amino)-N-(2,6-dimethylphenyl)acetamide)). Due to the high selectivity of the Ru(Bpga) complex for tertiary C-H, the reaction afforded a mixture of 25-, 20-, 17-, and 14-oxygenated cholesterols that could be easily separated by high-performance liquid chromatography. These results suggest that late-stage C-H oxidation could be a viable strategy for preparing candidate metabolites of biologically important molecules.

Ozone Oxidation of Silylalkene: Mechanistic Study and Application for the Synthesis of Silacarboxylic Acid Derivatives.

The addition-type ozone oxidation of silylalkenes is a highly efficient reaction to provide synthetically versatile α-silylperoxy carbonyl compounds. To gain insight into the reaction mechanism, we performed a computational study, which revealed that the reaction proceeds via [1,2]-Brook rearrangement-type silyl migration of primary ozonide. In sharp contrast to the addition-type reactions, the ozone oxidation of α-alkoxysilylalkenes proceeds in a cleavage-type manner to afford excellent yields of silacarboxylic acid esters via the 1,3-cycloelimination of primary ozonide prior to 1,2-silyl migration.

Natural dolapyrrolidone: Isolation and absolute stereochemistry of a substructure of bioactive peptides.

During the course of our chemical analysis of the hydrophilic fractions from marine cyanobacterium Moorena producens, we have isolated natural dolapyrrolidone (Dpy, 1), a natural pyrrolidone derived from phenylalanine, for the first time as a single compound. Compound 1, with an (S)-l absolute stereochemistry, was previously identified as a substructure that is common among several bioactive natural peptides. Surprisingly, the absolute stereochemistry of the isolated natural 1, determined through total synthesis, was (R)-d. This result was unambiguously determined by HPLC analysis using a chiral stationary column by comparing the retention times of the natural 1 and authentic samples of synthetic enantiomers. To verify the unexpected result, the absolute stereochemistry of the natural 1 was confirmed by X-ray crystallographic analysis of Pt-complex derivative using the synthetic enantiomer.

Bridged Stilbenes: AIEgens Designed via a Simple Strategy to Control the Non-radiative Decay Pathway.

To broaden the application of aggregation-induced emission (AIE) luminogens (AIEgens), the design of novel small-molecular dyes that exhibit high fluorescence quantum yield (Φfl ) in the solid state is required. Considering that the mechanism of AIE can be rationalized based on steric avoidance of non-radiative decay pathways, a series of bridged stilbenes was designed, and their non-radiative decay pathways were investigated theoretically. Bridged stilbenes with short alkyl chains exhibited a strong fluorescence emission in solution and in the solid state, while bridged stilbenes with long alkyl chains exhibited AIE. Based on this theoretical prediction, we developed the bridged stilbenes BPST[7] and DPB[7], which demonstrate excellent AIE behavior.

Differentiation-inducing factor-1 suppresses cyclin D1-induced cell proliferation of MCF-7 breast cancer cells by inhibiting S6K-mediated signal transducer and activator of transcription 3 synthesis.

Differentiation-inducing factor-1 (DIF-1) has been reported to inhibit the proliferation of various mammalian cells by unknown means, although some possible mechanisms of its action have been proposed, including the activation of glycogen synthase kinase-3 (GSK-3). Here, we report an alternative mechanism underlying the action of DIF-1 in human breast cancer cell line MCF-7, on which the effects of DIF-1 have not been examined previously. Intragastric administration of DIF-1 reduced the tumor growth from MCF-7 cells injected into a mammary fat pad of nude mice, without causing adverse effects. In cultured MCF-7, DIF-1 arrested the cell cycle in G0 /G1 phase and suppressed cyclin D1 expression, consistent with our previous results obtained in other cell species. However, DIF-1 did not inhibit the phosphorylation of GSK-3. Investigating an alternative mechanism for the reduction of cyclin D1, we found that DIF-1 reduced the protein levels of signal transducer and activator of transcription 3 (STAT3). The STAT3 inhibitor S3I-201 suppressed cyclin D1 expression and cell proliferation and the overexpression of STAT3 enhanced cyclin D1 expression and accelerated proliferation. Differentiation-inducing factor-1 did not reduce STAT3 mRNA or reduce STAT3 protein in the presence of cycloheximide, suggesting that DIF-1 inhibited STAT3 protein synthesis. Seeking its mechanism, we revealed that DIF-1 inhibited the activation of 70 kDa and/or 85 kDa ribosomal protein S6 kinase (p70S6K /p85S6K ). Inhibition of p70S6K /p85S6K by rapamycin also reduced the expressions of STAT3 and cyclin D1. Therefore, DIF-1 suppresses MCF-7 proliferation by inhibiting p70S6K /p85S6K activity and STAT3 protein synthesis followed by reduction of cyclin D1 expression.

Site-Selective Supramolecular Complexation Activates Catalytic Ethane Oxidation by a Nitrido-Bridged Iron Porphyrinoid Dimer.

Development of supramolecular methods to further activate a highly reactive intermediate is a fascinating strategy to create novel potent catalysts for activation of inert chemicals. Herein, a supramolecular approach to enhance the oxidizing ability of a high-valent oxo species of a nitrido-bridged iron porphyrinoid dimer that is a known potent molecular catalyst for light alkane oxidation is reported. For this purpose, a nitrido-bridged dinuclear iron complex of porphyrin-phthalocyanine heterodimer 35+ , which is connected through a fourfold rotaxane, was prepared. Heterodimer 35+ catalyzed ethane oxidation in the presence of H2 O2 at a relatively low temperature. The site-selective complexation of 35+ with an additional anionic porphyrin (TPPS4- ) through π-π stacking and electrostatic interactions afforded a stable 1:1 complex. It was demonstrated that the supramolecular post-synthetic modification of 35+ enhances its catalytic activity efficiently. Moreover, supramolecular conjugates achieved higher catalytic ethane oxidation activity than nitrido-bridged iron phthalocyanine dimer, which is the most potent iron-oxo-based molecular catalyst for light-alkane oxidation reported so far. Electrochemical measurements proved that the electronic perturbation from TPPS4- to 35+ enhanced the catalytic activity.

Internal-Edge-Substituted Coumarin-Fused [6]Helicenes: Asymmetric Synthesis, Structural Features, and Control of Self-Assembly.

π-Conjugated helicenes containing heteroatoms have attracted significant attention due to their diverse chemical and electronic structures, as well as tunable physical properties. It was rationally anticipated that the self-assembly of coumarin-fused helicenes would be controlled by the effects of a substituent on the internal edge of the helix. Here, this work reports the efficient syntheses of coumarin-fused helicenes 1 a,b (R=Ph, Me), and the enantioselective synthesis of 1 a (R=Ph) by chiral AuI -catalyzed hydroarylation. The helical structure of 1 was unambiguously determined by X-ray crystallography. Of particular note, the enantiomerically pure crystal of 1 a adopted a one-dimensional columnar structure based on π-π stacking interactions, as expected. Furthermore, a significant difference between the fluorescence quantum yields of the enantiomerically pure form and racemate of 1 a was observed.

Vinylidene ortho-Quinone Methides: Unique Chiral Reaction Intermediates in Catalytic Asymmetric Synthesis.

Vinylidene ortho-quinone methides (VQMs) are one-carbon elongated homologues of ortho-quinone methides (QMs), well-known as useful reaction intermediates in organic transformations. These related quinone methides are quite distinct in terms of stereochemistry. Namely, VQMs are characterized by an exocyclic allenyl ketone unit merged with a dearomatized ring system and thus, can be rendered axially chiral by locating a substituent properly at the terminal methylene group of the allene moiety. It should be also noted that VQMs are tautomers of ortho-ethynylphenols and these isomeric species are correlated through a proton-shift (tautomerization). Focusing on these stereochemical and structural features, we have pursued the development of unprecedented asymmetric reactions involving enantioenriched VQM intermediates generated by chiral-base-catalyzed tautomerization of the ethynylphenol precursors. Indeed, commonly used chiral base catalysts such as cinchonine (CN) and cinchonidine (CD) have been successfully demonstrated to be effective to this end. In this account, we wish to briefly describe our recent studies on the asymmetric syntheses of optically active indeno[1,2-c]chromenes, benzofuro[3,2-b]indeno[1,2-c]chromenes, and benzo[a]carbazoles, based on the catalytic enantioselective generation of VQMs with CN or CD and the stereocontrolled intramolecular follow-up cyclization with tethered alkynes, benzofurans, and indoles, respectively.

Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/ß-catenin signaling pathway.

We previously reported that celecoxib, a selective COX-2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/ß-catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analog that does not inhibit COX-2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-dependent transcription activity and suppressed the expression of Wnt/ß-catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh-/- mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/ß-catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs.

Construction of Condensed Polycyclic Aromatic Frameworks through Intramolecular Cycloaddition Reactions Involving Arynes Bearing an Internal Alkyne Moiety.

Facile synthetic methods for condensed polycyclic aromatic compounds via aryne intermediates are reported. The generation of arynes bearing a (3-arylpropargyl)oxy group from the corresponding o-iodoaryl triflate-type precursors efficiently afforded arene-fused oxaacenaphthene derivatives, which were formed through intramolecular [2+4] cycloaddition. Extending the method to the generation of arynes bearing a 1,3-diyne moiety led to a continuous generation of naphthalyne intermediate through the hexadehydro Diels-Alder reaction involving the aryne triple bond. This novel type of aryne-relay chemistry enabled the synthesis of a unique aminoarylated oxaacenaphthene derivative and highly ring-fused anthracene derivatives.

Oxygen Reduction to Water by a Cofacial Dimer of Iron(III)-Porphyrin and Iron(III)-Phthalocyanine Linked through a Highly Flexible Fourfold Rotaxane.

A µ-oxo-dinuclear iron complex of a supramolecular porphyrin-phthalocyanine conjugate was synthesized and its catalytic electrochemical oxygen reduction properties were investigated. In the conjugate, porphyrin and phthalocyanine units were connected to form a cofacial dimeric structure through a flexible fourfold rotaxane linkage, which was advantageous for accommodating small substrates between the iron centers. The conjugate showed efficient catalytic properties, at more positive potentials than those of other reported dinuclear porphyrinoid iron complexes, to selectively afford water through a four-electron reduction process.

The K-Region in Pyrenes as a Key Position to Activate Aggregation-Induced Emission: Effects of Introducing Highly Twisted N,N-Dimethylamines.

A new design strategy to activate aggregation-induced emission (AIE) in pyrene chromophores is reported. In a previous report, we demonstrated that highly twisted N,N-dialkylamines of anthracene and naphthalene induce drastic AIE when these donors are introduced at appropriate positions to stabilize the S1/S0 minimum energy conical intersection (MECI). In the present study, this design strategy was applied to pyrene: the introduction of N,N-dimethylamine substituents at the 4,5-positions of pyrene, the so-called K-region, are likely to stabilize MECIs. To examine this hypothesis, four novel pyrene derivatives, which contain highly twisted N,N-dimethylamino groups at the 4- (4-Py), 4,5- (4,5-Py), 1- (1-Py), or 1,6-positions (1,6-Py) were tested. The nonradiative transitions of 4,5-Py are highly efficient (knr = 57.1 × 107 s-1), so that its fluorescence quantum yield in acetonitrile decreases to Φfl = 0.04. The solid-state fluorescence of 4,5-Py is efficient (Φfl = 0.49). In contrast, 1,6-Py features strong fluorescence (Φfl = 0.48) with a slow nonradiative transition (knr = 11.0 × 107 s-1) that is subject to severe quenching (Φfl = 0.03) in the solid state. These results underline that the chemistry of the pyrene K-region is intriguing, both from a photophysical perspective and with respect to materials science.