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.
dissociation behavior of cocrystals is an essential task in particular during manufacturing
process of the solid dosage forms containing cocrystals as active
pharmaceutical ingredients (APIs). The authors have established the promising
technique with low-frequency Raman spectroscopy as a monitoring tool for
molecular state of APIs during wet granulation, which can detect the
dissociation of cocrystals successively and the rate calculated from the spectra
enabled to evaluate the stable cocrystal and the formulation with various
disintegrants. These findings would help researchers to consider developable
pharmaceuticals containing cocrystals.
An all-carbon quaternary stereocenter is found in many
biologically and pharmaceutically active compounds, in spite of being one of
the most difficult structures to construct in the field of synthetic organic chemistry.
In the present study, we were able to construct all-carbon quaternary stereocenters in an acyclic
system by utilizing a
face-selective alkylation of enolate intermediates derived from an asymmetric
Michael addition reaction of a chiral
lithium amide with trisubstituted α,β-unsaturated esters. Moreover, the obtained Michael adduct
was able to be converted to the β-amino ester having the all-carbon quaternary stereocenter by an oxidative deprotection.
The cover figure schematically illustrates the
divergent synthesis of various nitrogen-containing heteroaromatic marine
natural products by benzyne-mediated cyclization / functionalization cascade
reactions. The figure in the center is a slot machine, which represents
the flask used in the Cascade reaction, showing that several coins with the
structure of nitrogen-containing heteroaromatic complex marine natural products
are popping out when three numbers 7 hit at the same time.
Hospital preparations are frequently prepared in Japanese
hospitals, but quality evaluation is not necessarily sufficient. In this
article, quantitative 1H NMR spectroscopy (qNMR) was applied to the
quality evaluation of diclofenac gargles as an example of a hospital
preparation. Aliquots of the gargles were analyzed by qNMR using an internal
standard method, where the medicinal ingredients in the preparations were
accurately and precisely determined, with the water signal being effectively suppressed
by water suppression enhanced through T1
effects (WET). The quality and stability of the gargles were elucidated based
on the results. As such, qNMR with WET is potentially useful for the quality
control of various aqueous preparations because of its simplicity and
The authors have developed the
novel composite ordered-mixed (OM) particles containing fine drug-particles. The
composite OM particles were found to be double-structured spherical particles consisting
of finely-milled particles layered around the core particles. It was also found
that they have excellent characteristics from both pharmaceutical and micromeritic
perspectives and could overcome manufacturing problems of solid dosage forms. Such
unique OM particles could be precisely designed by ultra cryo-milling in liquid
nitrogen and subsequent mechanical powder processing which would be a potential
platform approach to develop the oral dosages (tablet, capsule, granule) with
improved dissolution property of poorly water-soluble drugs.
The authors developed ATRA reactions of
olefins with bromomalonate ester catalyzed by an in situ-formed halogen-bonding
complex. The use of 4-phenylpyridine as the halogen-bonding acceptor, the
desired reaction proceeded well under external irradiation of 380 nm LED light
to furnish the corresponding ATRA reaction product. The substrate activation
through the halogen bonding from the CT complex is a novel activation method
that can be used for challenging synthetic routes since halogen bond acceptors
such as pyridine are relatively inexpensive and readily available. This
approach offers a new strategy for other classes of compounds for photocatalysis,
including alkyl halides with amines or phosphine.
Biological membranes are an important target for
molecular design. Properly designed membrane-interacting peptides can induce
physicochemical and physiological responses in cell membrane and modulate cell
structure and function.
Previously, the authors developed a
cyclization reaction-based turn-on probe (TCC probe) for protein labeling. The
TCC probe is characterized by its ability to construct coumarin structures
easily by conjugate addition to the ynone moiety, but the reactivity of the
probe becomes poor when attempting to improve the fluorescence properties. The
authors improved the reactivity by increasing the electron-withdrawing property
of the leaving ester group and succeeded in constructing the coumarin skeleton
with good yields. These results suggest an easy method to introduce a coumarin
skeleton with good fluorescence properties.
Quality by design (QbD) is an
essential concept for modern manufacturing processes of pharmaceutical
products. Understanding the science behind manufacturing processes is crucial;
however, the complexity of the manufacturing processes makes implementing QbD
challenging. In this study, structural equation modeling (SEM) was applied to
understand the causal relationships between variables such as process
parameters, material attributes, and quality attributes. Based on SEM analysis,
a model composed of the above-mentioned variables and their latent factors without
including observational data was identified. The results indicate that SEM
analysis could be useful for implementing QbD for the manufacturing processes
of pharmaceutical products.
of the wide range of protein-protein interaction surfaces, it is important to
develop molecules that satisfy the intrinsic shape recognition of the partner
protein. The authors have previously shown that a stable non-naturally
occurring helix trimer of all trans-amide-bonded bicyclic β-amino acid inhibits
the p53-MDM2/MDMX-helix-helix interaction that plays a role in regulating p53
function. The authors showed herein that modification of the
C-terminal/N-terminal residues improved the inhibitory activity, and confirmed
that these peptides are membrane-permeable p53-MDM2/MDMX interaction
antagonists and can rescue p53 function in cells.
bioactivities of natural products are often beyond human knowledge and
imagination. In this article, the author developed original screening methods
based on protein binding activity. Protein beads method and protein plate
method were described. Protein beads method led to the discovery of neural stem
cell differentiation activators which inhibited Hes1 dimer formation as a new
mechanism. The author also developed protein plate method for protein-protein
interaction inhibitors to find new cancer drug candidates. Because protein
binding ability is tightly related to bioactivity, protein-based natural
products isolation is a powerful means to find new candidate medicines.
A cooperative catalyst comprising a soft Lewis acid/hard Brønsted
base enabled chemoselective activation of a hydroxyl group over an amino group.
The present chemoselective
catalysis could be applicable for a variety of amino alcohols, including
pharmaceuticals, without requiring a tedious
protection-deprotection process. Chemoselective enolization and subsequent α-functionalization
of carboxylic acid derivatives were also achieved by a redox active catalyst through
the radical process, providing unnatural α-amino/hydroxy
acid derivatives bearing a complex carbon framework and a diverse set of
functionalities. The present chemoselective catalysis described herein offers new
opportunities to expand the chemical space for innovative drug discovery
The optical property of fluorescent unit-conjugated
aliphatic oxaboroles has been investigated in this featured article. The authors
described the synthesis of fluorescent-oxaboroles by originally developed
methods and the optical behavior of the boroles with various sugars. The
oxaboroles provide good fluorescence quantum yields and selective recognition
toward D-ribose and D-ribose-containing molecules. The molecular recognition
induced significant fluorescence quenching. The authors also revealed the positive
correlation between the LUMO energy of the oxaborole and the relative
fluorescence intensity. The property of the boroles showed the possibility of
the boron-based NAD sensor probe.
Quantitative evaluation for
bitterness of pediatric medicine is essential for adherence.
The authors proposed criteria, change in concentration-dependent
potential (CCDP), dose-response slope of the sensor outputs of active
pharmaceutical ingredients measured by an
artificial taste sensor, which is new and useful bitterness evaluation index
for 48 pediatric medicines from the recent edition of the
WHO model list of essential medicines for children (7th ed., 2019). CCDP by individual
basic bitterness sensor well correlated to various physicochemical factors
related hydrophilicity and hydrophobicity. Therefore, CCDP proved to be useful
as a bitterness evaluation index of APIs in pediatric medicines.