Because lysine modifications on proteins
control various cellular processes and aberrations of the modifications are
associated with various diseases, chemical modulation of lysine-modifying
enzymes is interesting as a method to regulate the cellular functions or as a
therapeutic strategy. Therefore, the author has identified some modulators of
lysine-modifying enzymes. To find the modulators, the author has combined
conventional drug design with “strategic chemistry approaches,” such as drug
design based on enzyme catalytic mechanism. In this review, the author’s drug
discovery studies are presented.
describes that synthesis and evaluation of novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds as indirect AMP-activated
protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of
compounds inhibited cell growth of MDA-MB-453 but not that of SK-BR-3. The initial
structure optimization of the lead compound 4a led to the discovery of compound 4f with potent AMPK activation activity and poor aqueous solubility.
By further optimizing 4f, promising compound
25 was found out as a potent AMPK activator
EOD-1, produces large quantities of paramylon, has been reported to function as
a dietary fiber. However, the morphometric analysis of paramylon has not been
conducted so far. The authors attempted to
observe the detailed three-dimensional structure of paramylon by FIB/SEM. The
inside of paramylon particles was comprised of a dense structure with no
evidence of the presence of large pores and gaps. The specific surface area of paramylon particles was not as large as activated charcoal,
but similar to those of plant starches, indicating that the
cholesterol-lowering effect of paramylon cannot be simply attributed to its
The ubiquity of the biaryls with heteroatoms in and on the rings, are
of importance in organic chemistry as building blocks of functional compounds,
such as bioactive natural products, pharmaceuticals, and chemicals. Therefore, the cross-couplings can provide powerful tools for the
construction of biaryls and the development of a novel coupling method has been
intensively studied by synthetic chemists. In the present study, the author
demonstrated the metal-free oxidative couplings of two different aromatic C-H
bonds in electron-rich arenes for producing biaryls based on new strategies and
concepts using hypervalent iodine reagents.
Pharmacopoeias have provided public
standards to help ensure the quality of drugs. As of 2018, pharmacopoeias exist
in 56 countries and 3 regions. These pharmacopoeias have contributed to the
quality assurance of drug substances and products by providing common standards
for users in each region/country. As drug markets and supply chain is
independent standards in each pharmacopoeia increase users’ burden of having to
perform analytical procedures in different ways and using different acceptance
criteria to satisfy pharmacopoeia requirements that vary across regions. To contribute to the further convergence of pharmacopoeial
standards, the authors conducted a comparative
study of the pharmacopoeias in Japan, Europe, and the United States.
new triterpene glucosides and two megastigmanes were isolated from the leaves
of Diospyros maritima. The structures
of triterpene glucosides were elucidated by a sequential hydrolysis of
glycosidic and ester bonds using different enzymes to give partial hydrolyzed
intermediates and finally aglycones. Hydrolysis of 28-O-ester bonded glucose by a crude glucosidase may give a new tool
in triterpene chemistry. Two new
megastigmanes were also isolated and their structures were unambiguously
elucidated using the modified Mosher's method and two megastigmanes were
chemically correlated by NaBH4 reduction of the ketonic one.
Elucidation of functions of endogenous
peptides/proteins is undoubtedly valuable because they are key players of most
of biological pathways. The author has developed chemical biology tools to
accelerate the functional elucidation from the viewpoint of synthetic organic
chemistry. In this Featured Article, the author introduces following three
tools invented by his group: 1) an artificial amino acid that enables
stimulus-responsive functional control of peptides and proteins; 2) a traceable
linker for facile identification of target proteins of bioactive ligands; 3) an
in-cell compatible labeling reagent of proteins of interest.
Deprotonative coupling of pyridines with
electrophiles using a stoichiometric amount of strong Brønsted bases usually
employs cryogenic conditions in order to inhibit the occurrence of
side-reactions. In this paper, the authors established the efficient and convenient
coupling reaction of 3,5-dihalopyridines and
3-chloro-5-(trifluoromethyl)pyridine using an HMDS-amide base generated in situ
from a catalytic amount of CsF and a stoichiometric amount of N(TMS)3.
The reaction proceeds under ambient conditions and demonstrates the
applicability of various (hetero)arylaldehydes, pivalaldehyde, and
cyclohexanecarboxaldehyde as an electrophile.
A data science methodology to identify the
correct binding mode between CYP3A4 and compounds using deep learning has been
developed. The methodology enables us to predict the biding mode between a
substrate and CYP3A4 whose binding mode is difficult to predict with
conventional docking algorithms and binding mode scores mainly due to the
larger and more flexible biding pocket than that of the other CYPs.
guarantee the quality of crude drugs, the marker constituents for quality
control corresponding to each crude drug are defined. A standard product with a
fixed structure is indispensable for quality control of crude drugs, but the
structure of the standard product is unclear in a few cases. The authors found
multiple standards for polygalaxanthone III, which is a component of Onji's
marker constituent for quality control, and concluded from NMR and MS/MS
spectral analyses that their structures were polygalaxanthone III and
polygalaxanthone XI. In this study, they propose the use of LC-MS/MS to
distinguish polygalaxanthone III and XI.
A new catalytic system comprising chiral Ag Lewis acid and lithium
Brønsted base is developed for the synthesis of β2,2-amino acids by direct Mannich-type reaction of isoxazolidin-5-ones.
Two nitrogen atoms in the product are chemically distinctive and can be easily
differentiated. The cover art illuminates these
features of this work by a projection onto a mysterious space.
Membrane curvature is involved in variety of cellular phenomena. Peptide-based
sensors are useful that easily detect or visualize membrane curvatures in cell-related
studies. These have advantages over protein-based sensors in terms of the
compactness with smaller steric hindrance in their target recognition and the capabilities
of chemical modification and easy handling. In this article, a
structure–activity correlation study by the authors has led to an amphipathic peptide
FAAV that recognizes high-curvature membranes. The FAAV may be a promising
prototype of curvature sensors, which enable the capture of the dynamics and
roles of membrane curvatures in our life.
a-Helix-a-helix interactions are frequently observed at
protein-protein interfaces, and the p53-MDM2/MDMX interaction is considered to involve interactions between a-helix structures of p53 and MDM2/MDMX. This
work showed herein even non-naturally occurring artificial helix of bicyclic β-proline
oligomer derivatives, bearing pitch
and diameter per turn different from the typical a-helix structure of a-amino acid peptides can
structure sufficiently to interfere with the p53-MDM2/MDMX interaction.
The design of controlled-release particles is
required for developing orally disintegrating tablets (ODT). The authors have focused on melt
adsorption technique which affords precise control of the size distribution of controlled-release
particles and requires neither solvents nor drying processes. In the present study, the authors demonstrated that melt
adsorption is a superior manufacturing method for controlled-release particles. Specifically, ODT with
adequate strength and disintegration could be prepared by using the particles
which have been optimized by Design of Experiment (DoE) and Multiple regression
analysis without losing sustained-release. This technique should contribute to
the development of ODT to improve medication adherence.
Radiotheranostics means the integration
between diagnosis and therapy using radioisotopes. In the radiotheranostics,
the diagnostic probe and corresponding therapeutic probe should show similar
biodistribution. Thus, imaging using diagnostic probes before therapy can
predict therapeutic and side effects of corresponding therapeutic probes. The
author has developed radiolabeled probes with controlled pharmacokinetics for use
in radiotheranostics. In this article, bone-seeking probes, sigma-1 targeted
probes, and αVβ3
integrin targeted probes containing RGD peptide for cancer diagnosis and
therapy are introduced as radiotheranostic probes.
Determining the stereochemistry of a cyclic
acetal moiety is sometimes difficult because it is hard to observe NOESY
correlations depending on the substitution pattern and the conformation. While the
X-ray crystallographic analysis is a powerful method for structure
determination, many natural products are often
difficult to form single crystals because of their limited availability. The
authors accomplished the first asymmetric total syntheses of (+)-eurotiumide F
and (+)-eurotiumide G having such a cyclic acetal moiety, and through their
total syntheses, they succeeded to measure the X-ray crystallographic analysis
of eurotiumide G and revised the relative configuration between H1 and H4.
A methodologically and
conceptually novel immobilization method to prepare metal nano-particles (NPs)
catalyst are currently required for the development of organic, inorganic,
green, materials, and medicinal chemistry. Here the
authors developed” “in situ metal NP and nanospace
simultaneous organization (PSSO) method”, which is different from
previously reported metal NPs-immobilizing methods. They
also applied the in situ PSSO method
to prepare various immobilized transition-metal NPs, including base metals. For
example, the in situ PSSO method can
be applicable to easily prepare Pd, Ru, Ni, and Fe NPs with good recyclability
and low metal leaching for use in organic synthesis.
catalysts have attracted considerable attentions due to their low catalyst
loading and the high functional group compatibility. The authors conducted an
extensive research on the gold-catalyzed introduction of terminal alkynes to acetals
to reveal that thermally stable cationic gold catalysts bearing bulky ligands
were particularly suitable for the reaction. Because of its high utility to
synthesize a broad range of propargylic ethers, this protocol should find a
widespread use for synthesis of various propargylic ethers in the area of chemical
biology and medicinal chemistry.
The covalent bond formation (crosslinking) of
mRNA with the antisense oligonucleotide promotes the translational inhibition.
In this study, several derivatives of T-vinyl
(4-vinylpyrimidin-2-one) were investigated to obtain the stable derivative so
that its reactivity is protected until it access to the target site. Thus, the
2-thiopyrimidinyl T-vinyl derivatives was determined to be a good cross-linking
a moderate stability. The investigation using the
Luc mRNA, the synthetic mRNA and non-cellular translation system revealed that
the translation is terminated at the end of the cross-linked duplex between the
mRNA and the oligonucleotide.
Longgu is a fossil
crude drug used in Kampo prescriptions, but its role in the decoction is still
unclear. The authors hypothesized that it
adsorbs foreign organic compounds into its superficial pores, and aimed to
reveal it indirectly by 1H magic angle spinning NMR spectroscopic
analysis, thermogravimetric analysis and nitrogen adsorption isotherm. These
analyses revealed that longgu was macroporous material,
and it adsorbed organic compounds during the decoction process. Although
further study is required, the authors suggest
that the significance of longgu is in adjusting the component profiles in Kampo
decoctions as an adsorbent.