Cycloaddition-based Formal C–H Alkynylation of Isoindoles Leading to the Synthesis of Air-stable Fluorescent 1,3-Dialkynylisoindoles

Reaction of <i>N</i>-alkylisoindoles with (bromoethynyl)triisopropylsilane afforded 1,3-bis(triisopropylsilylethynyl) isoindoles in high yields. The formal C–H alkynylation proceeds under transition-metal-free conditions through [4 + 2] cycloaddition of the pyrrole ring of isoindole with bromoalkyne followed by ring-opening of the product

Cycloaddition-based Formal C–H Alkynylation of Isoindoles Leading to the Synthesis of Air-stable Fluorescent 1,3-Dialkynylisoindoles

Reaction of <i>N</i>-alkylisoindoles with (bromoethynyl)triisopropylsilane afforded 1,3-bis(triisopropylsilylethynyl) isoindoles in high yields. The formal C–H alkynylation proceeds under transition-metal-free conditions through [4 + 2] cycloaddition of the pyrrole ring of isoindole with bromoalkyne followed by ring-opening of the product

Characterization of Lactococcus garvieae isolated from radish and broccoli sprouts that exhibited a KG(+) phenotype, lack of virulence and absence of a capsule

Aims: To identify Lactococcus garvieae isolates from radish and broccoli sprouts and compare them with virulent and less virulent mutant strains obtained from yellowtails with regard to KG phenotype, presence of a capsule and virulence towards yellowtails and mice. Methods and Results: Comparative 16S rRNA gene sequence analysis of six isolates obtained from radish and broccoli sprouts indicated that they were L. garvieae (similarity >99%). They were compared with KG9502, Lg2 and ATCC49156 strains obtained from yellowtails. A less virulent mutant strain Lg2-S was obtained by Lg2 subculture. Biochemical characterization of the six strains resembled that of KG9502, Lg2, ATCC49156 and Lg2-S, except for saccharose and tagatose acidification and the presence of hippuricase. These six strains were nonpathogenic towards yellowtails and mice, nonsusceptible to bacteriophages and demonstrated heterogeneity on pulsed-field gel electrophoresis analysis. Using transmission electron microscopy, a capsule was observed in KG9502 and Lg2 but not in ATCC49156 and Lg2-S. Conclusions: We isolated L. garvieae strains that lacked pathogenicity towards yellowtails and mice from radish and broccoli sprouts; these were noncapsulated and exhibited KG+ phenotype. Significance and Impact of the Study: This is the first documentation of L. garvieae isolated from terrestrial plants. These isolates exhibited genetic diversity; however, they were noncapsulated and nonpathogenic towards yellowtails and mice

Plasma progastrin‐releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis‐targeted agents in patients with metastatic castration‐resistant prostate cancer

Abstract Background The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration‐resistant prostate cancer (CRPC) progression. The neuromediator, gastrin‐releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin‐releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis‐targeted (ARAT) agents. Methods One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first‐line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate‐specific antigen (PSA) response and survival estimates. Results In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: −34.5% vs. low ProGRP: −85.7% p = .033). PSA progression‐free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA‐PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA‐PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003). Conclusions Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA‐ and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research

Development of a manufacturing process toward the convergent synthesis of the COVID-19 antiviral Ensitrelvir

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route in the medicinal synthetic stage, the overall yield of the longest linear sequence (six steps) was improved by approximately 7-fold. Furthermore, nine out of the twelve isolated intermediates were crystallized directly from each reaction mixture without any extractive work-up (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19