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
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
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
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.
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
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.
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Optimization of our previous lead compound led to identification of DS68702229, a potent NAMPT activator with good oral exposure. Oral administration of DS68702229 to high-fat diet-induced obese mice elicited NAD+ level increase in various tissues, ultimately leading to continuous and significant body weight reduction. These observations indicate that DS68702229 is a promising anti-obesity drug candidate.
Control of site selectivity, selectivity among several identical functional groups, in molecular transformation has become a fundamental issue in synthetic organic chemistry owing to the potential utility for selective modification of biologically active multi-functionalized molecules. In the review article, the authors’ research related to site selectivity in two types of transformations, namely, the acylation of hydroxy groups and C-H amination, is summarized. In catalyst-controlled site-selective transformation, the catalysts choose the reaction point where they feel most comfortable.
A variety of topics have been reviewed from the view point of analytical chemistry. The topics include: self-reproducing vesicles led by molecular transformation, characterization and physiological roles of oxidized phospholipids, advantages of small fish as a carcinogenesis model, separation techniques in supercritical fluid chromatography, drug-antibody ratio determination of antibody-drug conjugates, and membrane-based rapid test reagents for point of care testing. All these reviews will provide indispensable information based on analytical chemistry that supports and evolves pharmaceutical sciences as well as biology and medicine.
Accurate quantitative and qualitative analysis of biological and clinical samples is important, and rapid and simple analytical methods are demanded. The authors investigate an electrochemical detection of alcohols and amines by cyclic voltammetry at low potential using nortropine N-oxyl (NNO) and a copper salt as catalysts. As a result, although the concentration that could be quantified with good accuracy was limited in both the detection of alcohols and the detection of amines, a correlation was observed between the current and the concentration.
α,β-Unsaturated carbonyl compounds undergo nucleophilic reaction at electron-deficient carbon-carbon double bonds, as well as cycloaddition with dienes or 1,3-dipoles having a high HOMO energy levels. This character of the enones and enals can be transformed from electron-deficient to electron-rich by conversion to the corresponding oximes because of the electron-donating ability of an electron pair (umpolung). This paper describes that α,β-unsaturated oximes underwent electrophilic epoxidation with in-situ-generated dimethyldioxirane to give the corresponding epoxides in good yields. Nucleophilic ring-opening reactions of the epoxides afforded α-substituted products. Shi asymmetric epoxidation of the oximes proceeded with moderate asymmetric selectivity.
Authors uses computational chemistry to scrutinize the biosynthetic mechanism of a diterpenoid, spiroviolene, which features a 5/5/5/5 tetracyclic system with a spirocyclic skeleton. Terpenes/terpenoids are biosynthesized via multiple stable carbocation intermediates, such as tertiary, allyl, and cyclopropylcarbinyl cations. However, formation of secondary carbocations have been proposed in the spiroviolene biosynthesis in earlier reports. On the basis of DFT calculations, authors propose a new 16-step carbocation cascade leading to the spiroviolene skeleton. This cascade bypasses the formation of unstable secondary carbocations by breaking the adjacent C–C bond to form a more stable tertiary carbocation and by Wagner-Meerwein 1,2-methyl rearrangement.
hybrid catalysts have been designed based on the reaction mechanism of enzymes.
These catalysts using non-covalent intermolecular interactions exhibit
remarkable catalytic performance for the activation of α,β-unsaturated amides and carboxylic
acids as well as the dynamic kinetic resolution of a racemic electrophile in an
SN2-type reaction. These innovative
catalytic systems allow the asymmetric synthesis of biologically important
molecules such as atorvastatin, beraprost,
sitagliptin, and avenaol.
In Japan, environmental risk assessments
(ERA) for human pharmaceuticals in aquatic environments have barely begun. This
paper reports the first study assessing the validity of ERA guidance issued by
the Ministry of Health, Labour, and Welfare in 2016 for new medicinal products
in the environment, using selected pharmaceuticals already on the market. The
accuracy of predicted environmental concentrations was evaluated by measuring
environmental concentrations in urban rivers. The results will be useful information
applicable to ERA for new medicinal products, and development of future ERA
standards in Japan.
PIM kinases are attractive therapeutic targets for the
treatment of multiple hematological malignancies. In search for novel PIM
kinase inhibitors, the authors designed and synthesized a series of 5-benzylidene-2-thioxothiazolidin-4-one
derivatives with various substitutions at the pyrazine rings. Several compounds
exhibited subnanomolar to single-digit nanomolar potencies against all three
PIM isoforms and showed anti-proliferative activities against human
leukemic EOL-1 and MOLM-16 cell lines. The mechanism of action study of compound
17 clearly revealed that a pan-PIM
inhibitor reduced phosphorylation of downstream substrates of PIM kinase such
as BAD and 4EBP1 in a dose-dependent manner.