Understanding the
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
convenience.
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.
Because
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.
Structure and
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
research.
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.
Novel 25 derivatives of puberulic acid were synthesized by utilizing the
authors’ total synthetic route. According to previous structure-activity
relationships information, they focused on the carboxylic acid moiety in puberulic
acid and converted it into the corresponding esters, amides and ketones. Antimalarial
evaluations in vitro and in vivo of these derivatives were
carried out and revealed detailed SAR information. It was clarified that
several ester and ketone derivatives conserve strong antimalarial activity
similar to that of puberulic acid without any obvious toxicity in oral dose of
15 mg/kg.
This present
review aims to achieve a comprehensive and up-to-date investigation in the
phytochemistry and pharmacology of Rosa laevigata Michx.. To date, phytochemical
investigation has exposed the presence of triterpenoids, flavonoids, tannins,
ligands and polysaccharides in this plant. The crude extracts and the purified compounds have
demonstrated various pharmacological effects
in vitro and in vivo. In conclusion, the chemical profiles together with the modern
pharmacological properties have been adequately summarized. These evidences have
revealed this plant to be a valuable source for therapeutic foodstuff and more attention should be paid to a better utilization
of this plant.
Structurally diverse
fungal meroterpenoids are promising drug seed
compounds. To obtain unnatural, novel meroterpene scaffolds, the authors tested
combinatorial biosynthesis by co-expressing functionally distinct terpene
cyclase (TPC) genes, pyr4, ascF, andB, or cdmG, with the
biosynthetic genes for the production of a TPC substrate, (10’R)-epoxyfarnesyl-dimethylorsellinic
acid-3,5-methyl ester, in Aspergillus
oryzae NSAR1 as a heterologous host. As a result, all of the tested TPCs
afforded the same two novel mono-cyclization products. This study provides
important information on the substrate scope of the TPCs, and will contribute
to the production of unnatural, novel molecules for future drug discovery.
The
authors developed solifenacin succinate functional drug particles embedded in a
gelling–swelling layer (PEGS) made of a three-layer structure consisting of a
core drug layer, a gelling–swelling layer, by which both adequate taste-masking
of drug and rapid drug elution were successfully achieved. They also optimized
incorporation of above PEGS into orally disintegrating tablets (ODTs), by usage
of a fibre-shaped microcrystalline cellulose with poor fluidity, which improved
the content uniformity of the ODTs, as the crystal fibres became entangled with
the PEGS and other additives.
Overall,
this taste masking system is so unique and propose new platform for taste
masking formulation.
A methanol extract from the underground part of
Calanthe discolor Lindl.
(Orchidaceae) demonstrated significant proliferative activity against human hair follicle dermal
papilla cells (HFDPC). Through bioassay-guided separation of the
extract, a new indole glycoside named 6′-O-b-D-apiofuranosylindican
was isolated along with six known compounds including three indole glycosides. Among
the isolates, three indole glycoside such as 6′-O-b-D-apiofuranosylindican,
glucoindican, and calanthoside showed significant proliferative activity.
Furthermore, these active indole glycosides upregulated the expression of VEGF
and FGF-7 mRNA and protein in HFDPC, which could be the mechanism of their proliferative
activity.
This
manuscript reports aerobic oxidation of primary alcohols into aldehydes with
nitroxyl radical/copper catalysis. The reaction method reported herein features
that the optimum nitroxyl radical/copper salt catalyst combinations differ
depending on the substrate.
To
express this feature, the catalytic reaction field is represented as a circus
tent with three shapes of windows, namely, circle, triangle, and square. Copper
plates with different nitroxyl radicals are placed under each of the windows,
which indicates different nitroxyl radical/copper salt catalyst combinations.
Different alcohol substrates are represented in different forms, namely,
sphere, tetrahedron, cube. The sphere, tetrahedral, and cubic alcohols pass
through the circular, triangular, and square windows, respectively, to be
oxidized into aldehydes.