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.
Natural products are potential sources of
lead compounds, especially intractable chemotherapeutic targets that require
molecules with three-dimensional diversity rather than flatter “drug-like”
molecules. This review article highlights the author’s efforts toward
establishing synthetic routes to natural anti-tuberculosis and anti-tumor
products, including structure−activity relationship
studies. The synthetic targets, caprazamycin C, intervenolin, and leucinostatin
A, exhibit striking biologic properties, such as antibacterial activity toward
highly resistant strains of tuberculosis and interference with growth signals
from stromal cells to tumor cells.
The author developed a series of vitamin D
analogues which act as agonist, partial agonist, or antagonist for vitamin D
receptor (VDR). The author examined the structures of the ligand-binding domain
(LBD) of VDR complexed with the analogues by the X-ray crystal structural
analysis, and small-angle X-ray scattering analysis combined with molecular
dynamics simulation. All states of the VDR-LBD, which include agonist-, partial
agonist- and antagonist-binding structures and apo-state structure, were clarified.
Thus the author elucidated the mechanisms of VDR agonism, partial agonism, and antagonism
based on structural changes (differences) in VDR-LBD induced by ligand binding.
The novel progesterone receptor antagonists based on the multi-template approach were developed. Multi-template strategy enables facile structure-activity relationship (SAR) investigation, and phenylamino-1,3,5-triazine scaffold is a useful core structure for development of transcription modulators targeting nuclear receptors.
Light controllable compounds are very useful tools to manipulate biological signaling. In this paper, authors showed the biological applicability of a yellowish-green light controllable NO releaser, NO-Rosa5, which is more readily synthesizable and efficient NO releaser than its prototype, NO-Rosa1. NO-Rosa5 showed less toxicity in MTT assay than a blue light controllable NO releaser, NOBL-1, and was applicable to photoinduced NO release control in cellular condition. Furthermore, NO-Rosa5 could control vasodilation of rat aortic strip by light stimulation in Magnus test condition. NO-Rosa5 is expected to be useful chemical tool for NO research and utilized for innovative therapeutic method.
The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. In the course of the experiments, the authors found that T2 measurements could detect the difference between the amorphous and crystalline API; furthermore, it was effective in monitoring the transformation from amorphous to crystalline during a thermal stress test. From these findings, the authors concluded that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.
Although fluorine-containing aryl formates have currently flourished as pharmaceutical and agrochemical intermediates, there is limited number of bearable methods in a large scale synthesis. In this article, the authors developed new operationally secure preparation method for dichloromethyl alkyl ethers having long carbon chains, and direct formylation of fluorine-containing aromatics with those reagents, which are applicable in a large scale synthesis. The authors also showed a number of examples for O-formylation of fluorine-containing and non-fluorine-containing aromatics with those reagents and the mechanistic aspect was discussed. The present method is simple and straightforward for laboratory and industrial use.
This paper describes that the first total synthesis of 3-epi-Juruenolide C. The γ-lactone natural product, which was isolated from roots of Virola surinamensis, exhibits moderate antifungal activity against Cladosporium cladosporioides. The synthesis features a highly selective cross metathesis and the subsequent one-pot regioselective bromination, an intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel, and a face-selective hydrogenation using a homogeneous Wilkinson’s catalyst. The sequential synthetic procedures could be useful to complete the synthetic and biological studies of other related γ-lactone natural products.
Regioselective cyanation of simple and non-activated carbon–carbon bonds catalyzed by nickel complexes is described. This protocol enables to use of the substituted allenes for regio- and stereocontrolled transformations and their applications for cyclization, 3-component coupling reaction, heterocycle formation as well as natural product synthesis are demonstrated. The author reveals the origin of the above selectivity by axial chirality transfer process using optically active allenes as substrates. Steric bulk of substituents is found to be a key factor for discrimination of allenyl carbon–carbon double bonds in hydrometallation step.
This paper describes the development and validation of a method for measuring linezolid and its metabolites PNU-142300 and PNU-142586 in human plasma, using ultra-performance liquid chromatography (UPLC) method. This method enables the simultaneous measurement of these three components within 3 min. Further, plasma concentrations of linezolid, PNU-142300 and PNU-142586 in patients treated with linezolid could be measured. The developed method is a useful tool for therapeutic drug monitoring and clinical pharmacokinetic/pharmacodynamic (PK/PD) profiling of linezolid, as well as for dose optimization during treatment.
3-Alkenyl cephem compound is a pharmaceutical intermediate. It is typically crystalized by pH adjustment method. However, since the filtration time in the solid-liquid separator is a bottleneck in the production, there is a need to control crystal morphology while changing the pH. This study could be shorten filtration time by pH-modulation operation that repeating the crystallization operation in the vicinity of solubility. The obtained monodisperse particles were like a pseudo-growth body in which a large number of primary particles were aggregated and increased, rather than being a crystallite growth.