The application of
mass spectrometry has been reevaluated in the field of pharmaceutical research.
The recent launch of the EchoMS system, which combines an MS/MS system with an acoustic
nano-liter dispensing system, has enabled label-free high-throughput screening
(HTS) assays for disease-related enzyme reactions without time-consuming chromatographic
separation. As the search for therapeutic agents for COVID-19 is currently
underway, the authors conducted an HTS campaign for SARS-CoV-2 3CL protease using
this system. A library of 32,033 compounds was assayed in 12 hours, and several
inhibitors with antiviral activity were found in further cell-based assay.
Pathogenic scrapie PrP
(PrPSc) accumulates in the brain resulting in the prion disease
progression. SPECT imaging of PrPSc could non-invasively diagnose prion
disease. The authors developed novel radioiodinated styryl chromone (SC) and
vinyl pyridyl chromone (VPC) derivatives for PrPSc imaging. They
found that the SC derivatives possess affinity for PrPSc, while the
conversion to the VPC derivatives abolishes the affinity. These results
indicate that a single aromatic ring in the imaging agents can make a
significant difference in the recognition of PrPSc. [125I]SC-NHEtOH
was shown to be a potential scaffold for the further development of prion imaging
agents.
Because 40% of the world’s population is faced with
the risk of Dengue virus (DENV) infection and no drug has yet been approved,
development of an anti-DENV agent is a key priority for human health. In this
article, the authors revealed that a combination of 4’-thio-modification and
introduction of monophosphate prodrug skeleton to nucleoside analog, for
example 5-ethynyl-(1-b-D-ribofuranosyl)imidazole-4-carboxamide (EICAR), is
valuable tactic to develop an effective anti-DENV agent.
The authors designed and synthesized two
visible light-absorbing hypervalent iodines, and investigated their property of
photo-reaction. Since heavy atom-containing molecules cause a direct triplet
excitation, these molecules promoted photo-oxidation under the irradiation of wavelength
exceeding their singlet excitation region. The various photo-oxidations are
demonstrated: oxidation of primary and secondary alcohols, diol, and sulfoxide.
Furthermore, spectroscopic analysis including phosphorescence excitation, and density
functional theory calculations were performed to prove the reaction mechanism
of the photo-oxidation in detail.
In this review, the author summarized his protein
modification studies over the past decade. By utilizing highly reactive
chemical species such as radical species and singlet oxygen, the author has
developed novel methods for the selective modification of tyrosine and
histidine residues, which have been difficult to be modified by conventional
methods. In addition, The author took advantage of the high reactivity of these
active species to apply protein modification reactions that proceed selectively
in the space of a few nanometers around the catalyst.
Surface plasmon resonance (SPR) sensors have been widely applied in various
fields of biotechnology and pharmacology, including drug discovery, biomarker
screening, virus detection, and food safety testing. In this report, a
metal-insulator-metal (MIM) type SPR sensor was fabricated by placing an
insulator layer on top of a gold thin film and then arranging gold colloidal
particles in a two-dimensional regular array on the insulator layer. Because of
resonance of the plasmons of the gold particles and the thin film, multiple
plasmon peaks/dips were observed. The substrate was shown to have twice the
sensing capability of the gold particles.
The
United Nations’ Sustainable Development Goals (SDGs) provide guidelines for
achieving a better and more sustainable future. Small-molecular drugs contribute
to SDG3 (“Ensure healthy lives and promote well-being for all at all ages”), and
waste reduction in small-molecular drug syntheses contributes to SDG6 (“Ensure
availability and sustainable management of water and sanitation for all”) . The
authors described an environmentally friendly scaled-up synthetic method for retinoid
X receptor agonist NEt-3IB, a candidate for treating inflammatory bowel
disease, by employing a reusable hydrophobic ether and ethanol.
Extracellular
polysaccharides (EPSs) are carbohydrate polymers secreted by bacteria, fungi and algae, and have various biological activities. EPSs from Leuconostoc mesenteroides subsp. mesenteroides strain NTM048 (NTM048 EPS) enhance IgA production of
mouse. In this study, the authors developed efficient synthetic routes to the
NTM048 EPS fragments and evaluated their effects on IgA-inducing activity. The
synthetic fragments showed a slight IgA-inducing activity, but the levels were not
as high as those of the NTM048 EPS, revealing that the activity by EPS might be
associated with the recognition of larger fragments or whole glucans, rather
than the recognition of glycan substructures.
The authors have isolated a new pentacyclic monoterpenoid indole
alkaloid glycoside, named secorubenine, from the heartwood of Adina rubescens,
a plant used as a traditional medicine in Southeast Asia. Its structure was
determined by careful analysis of the collected NMR spectra and chemical
modification of the isolated natural product. Furthermore, the enantioselective
total synthesis of secorbenine was immediately achieved by applying the
bioinspired total synthesis of monoterpenoid indole alkaloid glycosides
previously established by the authors. Thus, the exact structure of
secorubenine, including absolute stereochemistry, was confirmed.
A combination of biophysical techniques revealed various complex molecular interactions in membranes. Antimicrobial peptides form toroidal pores with surrounding lipids, followed by translocation into the cytosol. Amyloid β-protein recognizes clusters of monosialoganglioside GM1 on neuronal membranes, forming toxic amyloid fibrils containing 2-residue-shifted antiparallel β-sheets. The coiled–coil labeling method enables a quantitative analysis of membrane protein associations. The introduction of a GXXXG motif drives the formation of an otherwise unfavorable parallel dimer of a model transmembrane helix.
These current topics introduce the latest research on the liquid
chromatographic techniques utilized in food analysis. These liquid
chromatographic techniques are based on various detection methods including UV detection,
fluorescence detection, electrochemical detection and MS. These methods
incorporate innovations that go beyond simple chromatography, such as
derivatization to improve detectability of analyte, effective separation from
matrices by fluorous chemistry, multidimensional chromatography to separate a
wide range of polar compounds, and the use of methylated reference for the
determination without calibration curves using single reference liquid
chromatography. The contents of the topics would provide useful suggestions to improve
analysis of important ingredients in food samples.
The overestimation of osmium
is often observed in spike recovery test by ICP-MS. This is because osmium
formed the highly volatile osmium tetroxide in an oxidation reaction when microwave
digestion. The authors investigated the methods to stabilize osmium by using four
compounds, thiourea, ascorbic acid, sodium sulfite, and potassium
metabisulfite, that could reduce the overestimation of osmium isotopes. All
compounds were useful for stabilizing osmium and showed good spike recovery
results. The influence of adding compounds against other elements defined by
Q3D was also investigated.
The authors developed accurate and descriptive three types of gray-box
models to enhance process understanding and precise quality control in
fluidized bed granulation. These gray-box models were constructed by
integrating the heat and mass balance model (white-box model) and locally
weighted partial least squares regression (LW-PLSR) model (black-box model). Their
applicability was demonstrated using real operating data on a commercial scale
with two formulations. Furthermore, the authors proposed the assessment method
based on Hotelling’s T2 and Q residual for gray-box models using
LW-PLSR, which contributes decision support to select gray-box or white-box
model.
Lipid nanoparticles (LNPs) are able to
deliver various therapeutic macromolecules, including short interference RNAs,
mRNAs, and the clustered regularly interspaced short palindromic repeats (CRISPR)-associated
(Cas) ribonucleoproteins, into the cytosol of the target cells through
endocytosis followed by membrane fusion-mediated endosomal escape to induce
gene silencing, gene expression, and gene editing, respectively. Rational molecular
design of pH-sensitive cationic lipid was a major breakthrough that
dramatically increased delivery efficiency in this field. The LNPs would be
expected to be useful as a platform technology for the delivery of various
therapeutic modalities for genome editing and even for undiscovered therapeutic
mechanisms.
Catalysts have provided new modes of activation that enable the
transformation of otherwise inert molecules. Owing to the labile nature of the
N–O bond under reductive conditions, isoxazolidin-5-ones have been used as
useful b-amino acid surrogates. In
the last decade, this century-old heterocycle has experienced a renaissance
upon the merger with catalysis, allowing for the synthesis of structurally
diversified molecules otherwise difficult to obtain. This review article
highlights the author’s research in this emerging field, focusing on the
catalytic asymmetric a-functionalization of – and
the alkyl nitrene formation from – the heterocycle.
The author focuses on expanding
metal-carbene chemistry via developing novel reactions, mechanistic analysis based
on computational predictions, and synthetic demonstrations for pharmaceutically
essential molecules. The findings include that silver-carbenes possess unusual chemical
properties, leading to unique chemoselectivities and regioselectivities with
stereocontrol. By utilizing the exceptional reactivities, the enantioselective
reactions involving silver-carbenes were achieved in studies regarding arene
dearomatization. A novel type of insertion reactions was also developed using a
designed Rh2(NHCOtBu)4 catalyst,
assembling a series of nitrogen-bridged heterocycles. The author believes that
the obtained mechanistic profiles could serve as bases for designing novel
reactions and advanced catalysis for pharmaceuticals.
Chagas disease is a
neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi and an important health problem in rural
areas of Latin American countries. Safe drugs with high clinical efficacy have
been urgently needed. Authors
synthesized quinone compounds and evaluated their in vitro
antitrypanosomal activity against trypomastigotes and amastigotes of
Trypanosoma cruzi. In addition,
solubility and membrane permeability were measured to confirm whether compounds
with promising antiprotozoal activity had physicochemical properties compatible
with oral administration. Among the synthesized compounds, 5a showed adequate antiprotozoal activity, solubility, and high
membrane permeability.
The authors rationally
designed a series of curvature-sensing peptides, which could selectively
detect bacterial extracellular vesicles (EVs) in cultured media. The most sensitive peptide nFAAV5, in which the N-terminal region of the previosly reported curvature-sensing
peptide FAAV was modified, was applicable for quantification of changes in
the amount of EVs even in the presence of the EV-secretory bacterial cells. Therefore, the novel peptide is useful to EV studies as
a potent EV-sensing peptide.
In view
of self-medication, it is valuable to develop patient-friendly scored tablets
that possess dividing uniformity. Preparation conditions for a concavely curved
scored tablet were optimized, employing a design of experiment and a response surface
method incorporating a thin-plate spline interpolation, and a bootstrap
resampling technique. To make it possible to scaleup the optimal solution
estimated on a trial-scale, a Bayesian estimation was applied. Credible ranges
of critical responses in large-scale manufacturing were successfully estimated
as a posterior probability from the trial-scale experiment as a prior
probability.
Autophagy plays diverse
functional roles in various stages of tumor, and numerous drugs targeting
autophagy in in-vitro and in-vivo models for colorectal cancer (CRC)
have been reported. In search for novel
and effective drugs with minimal cytotoxicity to reduce the mortality rate of
CRC, the authors designed and synthesized a series of alkyl diamine linked
bivalent β-carbolines, and compound 8 was found to be the most potent antitumor
agent against human colon carcinoma cell lines with the IC50 value
of less than 5 μM. The mechanism of action study revealed that compound
8 reduced growth of colon cancer cells by inducing autophagy.