Photocatalytic Generation of Germyl Radicals from Digermanes Enabling the Hydro/Deuteriogermylation of Alkenes.

We have developed a visible-light-induced method to photolyze digermanes through single-electron oxidation using a photocatalyst, in contrast to direct excitation, to generate germyl radicals and achieve the hydro/deuteriogermylation of alkenes. This protocol allows the previously elusive incorporation of the small trimethylgermyl group and deuterium, metabolically stable bioisosteres of tert-butyl and hydrogen, respectively, making this approach attractive in not only organic synthesis but also medicinal chemistry.

Structural Revision of Tinotufolins from Tinospora crispa Leaves Guided by Empirical Rules and DFT Calculations.

Clerodane diterpenes are a class of secondary metabolites that can be classified into four types according to the configuration of the H3-19/H-10-H3-17/H3-20 fragment, i.e., trans-cis (TC), trans-trans (TT), cis-cis (CC), and cis-trans (CT). Tinotufolins A-C and E (1a-3a and 5a), isolated from the leaves of Tinospora crispa, were previously elucidated as CT-type clerodanes; however, our established 13C NMR-based empirical rules and density functional theory calculations suggested that these clerodanes belong to the CC type. Therefore, tinotufolins A-F (1-6) were reisolated from the leaves of T. crispa, along with an undescribed compound 7 and known compounds 8-11, and their structures were established by extensive spectroscopic analyses. The structures of tinotufolins A-C and E were revised to CC-type 1-3 and 5, and undescribed compound 7 was established as a CC-type clerodane. The present study demonstrates that empirical rules and calculations can efficiently identify and revise erroneous structures in clerodane diterpenes.

Comparison of Non-ephedrine Constituents from Ephedra Plants Cultivated in Japan.

Ephedra plants, the main components of which are ephedrine alkaloids, are used as traditional medicines in Eastern Asian countries. In this study, we isolated non-ephedrine constituents from various Ephedra plant species cultivated in Japan. HPLC analysis suggested that kynurenic acid and its derivatives accumulated in a wide range of Ephedra plant species. Furthermore, a large amount of (2R,3S)-O-benzoyl isocitrate has been isolated from E. intermedia. This study suggests that Ephedra plants have diverse non-ephedrine constituents.

Phytochemicals of Alpinia zerumbet: A Review.

Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm is a perennial plant of the Zingiberaceae family widely distributed in the subtropical and tropical areas of South America, Oceania, and Asia. Multiple plant parts of A. zerumbet have been traditionally used as medicinal sources, each with different clinical uses. These variations may arise from differences among the chemical components and/or accumulations of the active compounds in each part. Therefore, this review summarizes previous studies on the phytochemicals in A. zerumbet and reveals the similarities and differences among the chemical constituents of its multiple medicinal parts, including the leaves, rhizomes, fruits, seeds, and flowers. The results contribute to the scientific validation of the traditional understanding that A. zerumbet possesses different medicinal properties in each plant part. In addition, this review provides directions for further studies on the phytochemicals of this plant.

Characterization of the Volatile Constituents of Plai (Zingiber purpureum) by Gas Chromatography-Mass Spectrometry.

Zingiber purpureum Roscoe, known as plai in Thailand, is a perennial plant of the Zingiberaceae family and has traditionally been used in Southeast Asian countries to treat inflammation, pain, and asthma. In this study, we performed the characterization of the volatile constituents in ethyl acetate extracts of plai. Ethyl acetate extracts derived from the rhizomes of plai were subjected to gas chromatography-mass spectrometry, and the key peaks in the total ion current chromatograms were annotated or identified. In total, twenty-one compounds were identified using isolation procedures or standards, and nine compounds were annotated by comparing their Kovats retention index (RI) and electron ionization (EI) mass spectra with those in the literature. Most of the identifications were inconsistent with the tentative annotations found via library search and suggested that some peaks were incorrectly assigned in previous studies. Thus, to avoid further misannotations and contribute to the research on dereplication, the RI value, EI mass spectral data, and NMR spectroscopy data of the isolated compounds are reported.

Comprehensive Analysis of Sulfated Flavonoids in Eclipta prostrata for Quality Evaluation.

Eclipta prostrata (Asteraceae) is employed as a hemostatic agent in many traditional medicines, owing to its sulfated flavonoid content. In this study, we obtained crude drug samples from three provinces collected in different years and analyzed their sulfated flavonoid contents using liquid chromatography-mass spectrometry (LC-MS) for quality evaluation. Because sulfated flavonoids are unstable and difficult to isolate from extracts, this study first synthesized a variety of sulfated flavonoids and accumulated spectral data in order to identify the compounds in E. prostrata. The LC-MS analysis of six crude drug samples revealed the presence of luteolin 7-sulfate, apigenin 7-sulfate, diosmetin 7-sulfate, and diosmetin 3'-sulfate. The samples without luteolin 3'-sulfate featured high apigenin 7-sulfate content. Although the samples were collected from the same locality, their compositions differed depending on the year of collection. Further, they were classified according to three patterns: (1) samples with luteolin 7-sulfate as the main component, (2) samples with apigenin 7-sulfate as the main component, and (3) samples with relatively high diosmetin sulfate content. Luteolin 7-sulfate typically exhibits relatively high erythrocyte aggregation efficiency and fibrinogen aggregation rate. These results demonstrate that the analysis of sulfated flavonoids is beneficial for the quality evaluation of E. prostrata for hemostatic applications.

Enantioselective Construction of Tetrahydroindole Skeletons by Rh-Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes.

We have developed the Rh-catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide-tethered 1,6-enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio- and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O2 affords hexahydroindole-diols bearing three stereogenic centers and variable substituents on the nitrogen. Mechanistic studies have revealed that the substituents of the enynes change the ratio of intramolecular and intermolecular rhodacycle formation when using terminal alkynes, varying the ee values of the cycloadducts.

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate-Mediated Photocycloaddition.

Dearomative construction of multiply-fused 2D/3D frameworks, composed of aromatic two-dimensional (2D) rings and saturated three-dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8-tetrahydroquinoline (THQ)-based polycycles, and dearomative access to 1,2,3,4-THQ-based structures remains limited. Herein, we present a chemo-, regio-, diastereo-, and enantioselective dearomative transformation of quinolines into 1,2,3,4-THQ-based 6-6-4-membered rings without any catalyst, through a combination of nucleophilic addition and borate-mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

Photocatalytic Generations of Secondary and Tertiary Silyl Radicals from Silylboranes Using an Alkoxide Cocatalyst.

Silyl radicals are valuable species to prepare diverse organosilicon compounds. However, unlike stable tertiary silyl radicals, the use of secondary silyl radicals has been problematic in silylation reactions due to their instability. Here, we present photocatalytic in situ generations of both secondary and tertiary silyl radicals by one-electron oxidation of ate complexes, formed from silylboranes and an alkoxide cocatalyst, achieving highly efficient hydrosilylation and deuterosilylation of electron-rich alkenes and dienes as well as electron-deficient alkenes. The theoretical studies show that anionic borate complexes activated with an alkoxide have lower oxidation potentials than neutral borate complexes, allowing the formation of secondary silyl radicals. The calculated reaction pathways reveal that anionic conditions using the conjugate acid-base pair of NaOEt (cocatalyst) and EtOH (solvent) are the key to expanding the scope of silyl radicals and alkenes.

Homogeneous and Heterogeneous Gold Catalysis for Materials Science.

Often stoichiometric amounts of gold find use in materials science; occasionally gold is even used as a support. This review discusses the contributions of gold catalysis, both homogeneous and heterogeneous, to the field of materials science. One topic is the synthesis of polymers, including nanowires and polyesters, the postcyclization of polymers, polymerization by cyclopropanation, and gold-catalyzed radical polymerization reactions. Other topics are dyes, phosphonium salts, and a wide range of extended conjugated π-systems, the latter ranging from acenes, pentalene derivatives, and different heterocyclic π-systems to fascinating applications in the synthesis of helical anellated aromatic molecules. The existing contributions clearly demonstrate the potential of gold catalysis for significant future impulses for the field of materials science.

Attenuation of LPS-Induced Lung Injury by Benziodarone via Reactive Oxygen Species Reduction.

As overproduction of reactive oxygen species (ROS) causes various diseases, antioxidants that scavenge ROS, or inhibitors that suppress excessive ROS generation, can be used as therapeutic agents. From a library of approved drugs, we screened compounds that reduced superoxide anions produced by pyocyanin-stimulated leukemia cells and identified benzbromarone. Further investigation of several of its analogues showed that benziodarone possessed the highest activity in reducing superoxide anions without causing cytotoxicity. In contrast, in a cell-free assay, benziodarone induced only a minimal decrease in superoxide anion levels generated by xanthine oxidase. These results suggest that benziodarone is an inhibitor of NADPH oxidases in the plasma membrane but is not a superoxide anion scavenger. We investigated the preventive effect of benziodarone on lipopolysaccharide (LPS)-induced murine lung injury as a model of acute respiratory distress syndrome (ARDS). Intratracheal administration of benziodarone attenuated tissue damage and inflammation via its ROS-reducing activity. These results indicate the potential application of benziodarone as a therapeutic agent against diseases caused by ROS overproduction.

Effectiveness of Albumin-Fused Thioredoxin against 6-Hydroxydopamine-Induced Neurotoxicity In Vitro.

Parkinson's disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin-thioredoxin fusion protein (Alb-Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb-Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb-Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb-Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb-Trx pretreatment ameliorated these changes. Furthermore, Alb-Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb-Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb-Trx may have potential as a novel therapeutic agent for PD.

Identification of Anti-Inflammatory Compounds from Peucedanum praeruptorum Roots by Using Nitric Oxide-Producing Rat Hepatocytes Stimulated by Interleukin 1ß.

The roots of Peucedanum praeruptorum Dunn and Angelica decursiva Franchet et Savatier are designated Zenko, which is a crude drug defined by the Japanese Pharmacopoeia. This crude drug is used as an antitussive and an expectorant and is included in the Kampo formula Jinsoin, which improves cough, fever, and headache. Although the anti-inflammatory effects of this crude drug have been determined, the constituents responsible for this effect remain unknown. To investigate biologically active compounds, rat hepatocytes were used, which produce proinflammatory mediator nitric oxide (NO) in response to proinflammatory cytokine interleukin 1ß (IL-1ß). A methanol extract of P. praeruptorum roots, which suppressed IL-1ß-induced NO production, was fractionated into three crude fractions (ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions) based on hydrophobicity. The EtOAc-soluble fraction markedly inhibited NO production. After this fraction was purified, three biologically active compounds were identified as praeruptorins A, B, and E, the contents of which were high. A comparison of their activities indicated that praeruptorin B exhibited the highest potency to inhibit NO production by decreasing inducible NO synthase expression and suppressed the expression of mRNAs encoding proinflammatory cytokines. Collectively, the three praeruptorins may primarily contribute to the anti-inflammatory effects of P. praeruptorum roots.

[Two Cases of Femoral Nerve Palsy after Pelvic Surgery].

Postoperative femoral nerve palsy (FNP) is a rare complication associated with urologic surgery. Inappropriate use of retractors, use of lithotomy position, and prolonged surgery that lead to the femoral nerve compression have been reported as risk factors for FNP. Here, we report two cases of FNP after pelvic surgery. Case 1: A 47-year-old woman underwent ureterocystoneostomy for a giant ureterocele. On the first postoperative day, she developed muscle weakness and paresthesia in the left lower leg. An orthopedic surgeon diagnosed her with FNP associated with the surgery. Case 2: An 82-year-old woman underwent radical cystectomy for invasive bladder cancer. On the second postoperative day, she developed extension deficit in the left lower leg and was diagnosed with an iatrogenic FNP. Although this complication is infrequent, at onset, it leads to difficulty in walking and gait disturbance in the patient. As a result, it greatly reduces the patient's postoperative quality of life. Therefore, preventive measures should be taken to reduce the risk of this postsurgical nerve injury, such as appropriate placement of retractors and proper patient positioning during the operation.

Rhodium-Catalyzed Chemo-, Regio-, Diastereo-, and Enantioselective Intermolecular [2+2+2] Cycloaddition of Three Unsymmetric 2π Components.

We have developed the Rh+ /H8 -binap-catalyzed chemo-, regio-, diastereo-, and enantioselective intermolecular [2+2+2] cycloaddition of three unsymmetric 2π components. Thus, two arylacetylenes react with a cis-enamide to yield a protected chiral cyclohexadienylamine. Moreover, replacing one arylacetylene with a silylacetylene enables the [2+2+2] cycloaddition of three distinct unsymmetric 2π components. These transformations proceed with excellent selectivity (complete regio- and diastereoselectivity and up to >99 % yield and >99 % ee). Mechanistic studies suggest the chemo- and regioselective formation of a rhodacyclopentadiene intermediate from the two terminal alkynes.

Shape- and Size-Tunable Synthesis of Covalent Organic Cages through Rh-Catalyzed Regioselective [2+2+2] Cycloaddition.

Covalent organic cages have potential applications in molecular inclusion/recognition and porous organic crystals. Bridging arene units with sp3 atoms enables facile construction of rigid isolated internal vacancies, and various prismatic arene cages have been synthesized by kinetically controlled covalent bond formation. However, the synthesis of a tetrahedral one, which requires twice as much bond formation as prismatic ones, has been limited to a thermodynamically controlled dynamic SN Ar reaction, and this reversible covalent bond formation made the resulting cage product chemically unstable. Here we report the Rh-catalyzed high-yielding and highly 1,3,5-selective room temperature [2+2+2] cycloaddition of push-pull alkynes and its application to the synthesis of chemically stable aryl ether cages of various shapes and sizes, including prismatic and tetrahedral forms. These aryl ether cages are highly crystalline and intertwine with each other to form regular packing structures. Some aryl ether cages encapsulated isolated water molecules in their hydrophobic cavity by hydrogen bonding with the multiple ester moieties.

An Electron-Deficient CpE Iridium(III) Catalyst: Synthesis, Characterization, and Application to Ether-Directed C-H Amidation.

The synthesis, characterization, and catalytic performance of an iridium(III) catalyst with an electron-deficient cyclopentadienyl ligand ([CpE IrI2 ]2 ) are reported. The [CpE IrI2 ]2 catalyst was synthesized by complexation of a precursor of the CpE ligand with [Ir(cod)OAc]2 , followed by oxidation, desilylation, and removal of the COD ligand. The electron-deficient [CpE IrI2 ]2 catalyst enabled C-H amidation reactions assisted by a weakly coordinating ether directing group. Experimental mechanistic studies and DFT calculations suggested that the high catalytic performance of [CpE IrI2 ]2 is due to its electron-deficient nature, which accelerates both C-H activation and IrV -nitrenoid formation.

ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma.

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long-chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization-tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9-mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9-mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C-C motif) ligand-2 downregulation by AKT-mTOR-STAT3 signaling. Collectively, these results suggest that ELOVL5-mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.

Rhodium-Catalyzed Intermolecular Cycloaromatization Route to Cycloparaphenylenes that Exhibit Aggregation-Induced Emission.

A high-yielding new route to substituted cycloparaphenylenes has been developed via reductive aromatization of a diyne bearing two cyclohexadiene units giving a cyclophenylene-ethynylene (CPE) followed by the cationic rhodium(I)/dppe complex-catalyzed intermolecular [2+2+2] cycloaddition (cycloaromatization) of the CPE with monoynes. The thus-obtained products, substituted [8]cycloparaphenylene-triphenylenes ([8]CPPTs), exhibited definite aggregation-induced emission (AIE). This molecule is noteworthy as a novel AIE-active cycloarylene that does not have well-known AIE luminogens, such as tetraphenylethene and 1,2,4,5-tetraphenylbenzene skeletons. The single-crystal X-ray diffraction analyses of the AIE-active [8]CPPTs revealed their highly ordered packing structures in which the rotation of the triphenylene moieties is restricted.

Oxidative [4 + 2] annulation of 1-naphthols with alkynes accelerated by an electron-deficient rhodium(III) catalysts.

The 1,3-diethoxycarbonyl-2,4,5-trimethylcyclopentadienyl (CpE) rhodium(III) complex displayed high efficacy in the catalytic oxidative annulation of 1-naphthols with internal alkynes under mild conditions. DFT calculations revealed that lower activation energies for the concerted metalation-deprotonation and the reductive elimination steps are the key to improved reactivity.