Pyrroloindoline/Pyridoindoline Synthesis via C3-Dearomative Arylation/Cyclization of Tryptamine/Homotryptamine Derivatives Using Palladium-Dihydroxyterphenylphosphine Catalyst.

A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the dearomative C3-arylation of tryptamine derivatives with aryl nonaflates. The intramolecular cyclization of the resulting 3,3-disubstituted indolenines afforded C3a-arylated pyrroloindolines in one pot. We postulate that the formation of complexes between the lithium salts of DHTP and the tryptamine derivative is the key to promoting selective arylation at the C3-position of the indole ring. Furthermore, reactions using homotryptamine derivatives successfully provided C4a-arylated pyridoindolines.

Palladium-Catalyzed C-H Arylation of [1,1'-Biphenyl]-2-ols with Chloroarenes.

Palladium-catalyzed, hydroxy-group-directed C-H arylation of [1,1'-biphenyl]-2-ols with chloroarenes was performed. The reaction showed a broad substrate scope and was successfully applied to pharmaceuticals containing a chloro group. Using 2-heteroarylphenols instead of [1,1'-biphenyl]-2-ols also yielded the desired products. The arylated product was further transformed into a triphenylene derivative.

Synthesis of Symmetrical Sulfides Enabled by a Sulfur Dioxide Surrogate Acting as a Divalent Sulfur Source.

Herein, we present a safe and practical methodology for synthesizing symmetrical sulfides using iodoarenes and potassium metabisulfite (K2S2O5). While K2S2O5 is known as a convenient sulfur dioxide surrogate, here it acts as a divalent sulfur source, pioneering its potential utility. The reaction exhibits wide substrate generality in which even highly bulky substrates can be applied to afford sterically congested sulfides.

The production and secretion of tRNA-derived RNA fragments in the corn smut fungus Ustilago maydis.

The biogenesis of small non-coding RNAs is a molecular event that contributes to cellular functions. The basidiomycete fungus Ustilago maydis is a biotrophic pathogen parasitizing maize. A hallmark of its genome structure is an absence of RNAi machinery including Dicer and Argonaute proteins, which are responsible for the production of small RNAs in other organisms. However, it remains unclear whether U. maydis produces small RNAs during fungal growth. Here we found that U. maydis cells accumulate approximately 20-30 nucleotides of small RNA fragments during growth in the axenic culture condition. The RNA-seq analysis of these fragments identified that these small RNAs are originated from tRNAs and 5.8S ribosomal RNA. Interestingly, majority of their sequences are generated from tRNAs responsible for asparagine, glutamine and glycine, suggesting a bias of origin. The cleavage of tRNAs mainly occurs at the position near anticodon-stem-loop. We generated the deletion mutants of two genes nuc1 and nuc2 encoding RNase T2, which is a candidate enzyme that cleaves tRNAs. The deletion mutants of two genes largely fail to accumulate tRNA-derived RNA fragments. Nuc1 and tRNA are co-localized at the tip of budding cells and tRNA fragment could be detected in culture supernatant. Our results suggest that specific tRNAs would be cleaved during secretory processes and tRNA fragments might have extracellular functions.

Monitoring Gene Conversion in Budding Yeast by Southern Blot Analysis.

By using an inducible site-specific double-strand break (DSB) in budding yeast, it is possible to monitor-in real time-the repair of the break by homologous recombination. A method is described using an ectopic homologous donor sequence to repair an HO endonuclease-induced DSB. These gene conversion events can occur with or without crossing-over, the products of which are distinguished as different-sized restriction endonuclease fragments. The method of Southern blotting is described in detail.

Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl Chlorides, Triflates, and Nonaflates Using a Palladium-Dihydroxyterphenylphosphine Catalyst.

A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-unsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to accelerate the arylation at the C3 position. Reactions using 3-alkylindoles afforded 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives.

Synthesis of 2,2,5-Trisubstituted 2H-Pyrroles and 2,3,5-Trisubstituted 1H-Pyrroles by Ligand-Controlled Site-Selective Dearomative C2-Arylation and Direct C3-Arylation.

Palladium-catalyzed site-selective dearomative C2-arylation of 2,5-diaryl-1H-pyrroles with aryl chlorides was accomplished, and a series of 2,2,5-triaryl-2H-pyrroles were synthesized. In addition, the site selectivity of the reaction was switched by simply changing the ligand, and the direct C3-arylated 2,3,5-triaryl-1H-pyrroles were prepared. The obtained 2,2,5-triaryl-2H-pyrroles could be further transformed into 2,2,5,5-tetraarylpyrrolidines.

Network Rewiring of Homologous Recombination Enzymes during Mitotic Proliferation and Meiosis.

Homologous recombination (HR) is essential for high-fidelity DNA repair during mitotic proliferation and meiosis. Yet, context-specific modifications must tailor the recombination machinery to avoid (mitosis) or enforce (meiosis) the formation of reciprocal exchanges-crossovers-between recombining chromosomes. To obtain molecular insight into how crossover control is achieved, we affinity purified 7 DNA-processing enzymes that channel HR intermediates into crossovers or noncrossovers from vegetative cells or cells undergoing meiosis. Using mass spectrometry, we provide a global characterization of their composition and reveal mitosis- and meiosis-specific modules in the interaction networks. Functional analyses of meiosis-specific interactors of MutLγ-Exo1 identified Rtk1, Caf120, and Chd1 as regulators of crossing-over. Chd1, which transiently associates with Exo1 at the prophase-to-metaphase I transition, enables the formation of MutLγ-dependent crossovers through its conserved ability to bind and displace nucleosomes. Thus, rewiring of the HR network, coupled to chromatin remodeling, promotes context-specific control of the recombination outcome.

Change of Oral to Topical Corticosteroid Therapy Exacerbated Glucose Tolerance in a Patient with Plaque Psoriasis.

BACKGROUND Psoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption. CASE REPORT An 80-year-old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved. CONCLUSIONS Control of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications.

Palladium-Catalyzed Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl Chlorides and Triflates.

The direct C3-arylation of N-unsubstituted indoles with aryl chlorides and triflates has been realized using a palladium-dihydroxyterphenylphosphine (DHTP) catalyst. The site selectivity is different from that obtained with other structurally related ligands. This unique feature of the DHTP ligand is attributed to complex formation between the lithium salts of the ligand and the indole. The method was applied to the late-stage derivatization of pharmaceuticals having a chloro group.

Three-step synthesis of 2,5,7-trisubstituted indoles from N-acetyl-2,4,6-trichloroaniline using Pd-catalyzed site-selective cross-coupling.

We report a facile three-step synthesis of 2,5,7-trisubstituted indoles from N-acetyl-2,4,6-trichloroaniline, with the first step featuring Pd/dihydroxyterphenylphosphine (DHTP)-catalyzed ortho-selective Sonogashira coupling followed by cyclization to afford 2-substituted 5,7-dichloroindoles. Subsequent introduction of aryl or alkenyl groups at the C7 position was achieved by Pd/DHTP-catalyzed site-selective Kumada-Tamao-Corriu coupling, with further substitution of the chlorine at the C5 position (Suzuki-Miyaura coupling or Buchwald-Hartwig amination) affording 2,5,7-trisubstituted indoles.

One-Pot Synthesis of Substituted Benzo[b]furans and Indoles from Dichlorophenols/Dichloroanilines Using a Palladium-Dihydroxyterphenylphosphine Catalyst.

Disubstituted benzo[b]furans were synthesized by ortho-selective Sonogashira coupling of dichlorophenols and terminal alkynes, followed by cyclization and Suzuki-Miyaura coupling in one pot, using a palladium-dihydroxyterphenylphosphine (Cy-DHTP) catalyst. The use of substoichiometric amounts of tetrabutylammonium chloride was effective in accelerating the Suzuki-Miyaura coupling. This protocol was also successfully applied to the one-pot synthesis of disubstituted indoles from dichloroaniline derivatives.

Three-Step Synthesis of Fluoranthenes through Pd-Catalyzed Inter- and Intramolecular C-H Arylation.

A three-step synthetic method for the preparation of fluoranthenes, involving Miura's intermolecular C-H arylation, nonaflation, and intramolecular C-H arylation, has been developed. Various 1-naphthols and haloarenes were successfully used as substrates. Reaction conditions that afford high site selectivity have been developed for the intramolecular C-H arylation step.

Ligand-Controlled Site-Selective Cross-Coupling.

Site-selective mono-cross-coupling reactions involving dichloro- or dibromo(hetero)aryl substrates are utilized to prepare substituted monochloro- or monobromo(hetero)arenes, which are used as drug components and synthetic precursors. In these reactions, selectivity toward the preferred reaction site of a dihalo(hetero)arene can vary depending on the ancillary ligand of the transition metal catalyst. This review summarizes the examples of ligand-controlled site-selective cross-coupling reactions, specifically those mediated by Pd complexes.

Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J).

AIM: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle-related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon-like peptide-1 receptor agonist that affects the histological findings in patients with non-alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy-proven NASH. METHODS: After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks. RESULTS: Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide. CONCLUSION: Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.

Identification of the cause of severe skin infection by Fournier transform infrared spectroscopy: a case of Fournier's gangrene caused by fish bone.

Fournier's gangrene (FG) is an infrequent but highly lethal infection. Here we report a 74-year-old man who presented with genital swelling and severe malaise. Based on the physical and imaging examination results, the diagnosis of FG was confirmed. Intraoperative findings showed dirty necrosis of soft tissue, and a splinter-shaped foreign body was found in the perirectal region. The foreign body was thought to be the cause of the condition, and it was analyzed using Fourier transform infrared spectroscopy. We found that the foreign body was a mixture of calcium phosphate and protein, suggesting that the splinter was a bone. Moreover, during the medical interview, the patient mentioned about intake of fish around the time of onset of symptoms. Therefore, to confirm the results of the analysis, DNA was extracted from the foreign body, and genomic PCR with subsequent sequence analysis was performed. The DNA sequence was identical to that of Oncorhynchus kisutch, a salmon that is a very popular food in Japan. On the basis of these findings, we concluded that FG in this case was caused by the penetration into the rectum of an accidentally ingested fish bone. Although some cases of intra-abdominal abscess due to accidental ingestion of fish bone have been reported, FG caused by fish bone is extremely rare.

Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells.

We report a case of an 88-year-old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death-1 (PD-1), Bcl-6 and CXCL13. Flow cytometry analysis showed that CD4(+) PD-1(hi) T cells also expressed CD10, inducible T-cell co-stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T-cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)-cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH-cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.

One-pot synthesis of 2,4-disubstituted indoles from N-tosyl-2,3-dichloroaniline using palladium-dihydroxyterphenylphosphine catalyst.

4-Chloroindoles were synthesized from readily available 2,3-dichloroaniline derivatives and terminal alkynes. The catalyst composed of palladium and dicyclohexyl(dihydroxyterphenyl)phosphine (Cy-DHTP) enabled ortho-selective Sonogashira coupling, and subsequent cyclization afforded 4-chloroindoles in high yields. This transformation was successfully applied to the one-pot synthesis of 2,4-disubstituted indoles via Suzuki-Miyaura coupling after indole formation.