The fungal meroterpenoid
biosynthetic pathways exhibit an abundance of unusual chemistries and
interesting enzyme reactions, including those of the multi-functional non-heme Fe(II)- and 2-oxoglutarate-dependent oxygenases that
perform selective C–H activation/functionalization
with unusual substrate promiscuity and catalytic versatility. Structure–function studies of these remarkable enzymes provide
an excellent platform for the development of useful biocatalysts for synthetic
biology to create novel molecules for drug discovery.
Rubbing actions are often conducted to apply
topical formulations onto the skin. However,
few studies have reported the reasons for the acceleration of drug permeation
through skin after topical application with or without rubbing. In addition, no
studies observed the effect of rubbing direction on the skin
penetration-enhancement effects. In this paper, the
authors investigated the
effects of rubbing direction on the skin permeation and disposition of a model
hydrophilic drug, caffeine. This paper provides useful
information on the effect of rubbing action and rubbing
direction on the skin permeation of topically applied drugs.
Marine dinoflagellates are well known as rich
sources of biologically active compounds possessing unique chemical structures.
This paper deals isolation and structure elucidation of two new cytotoxic 15-membered
macrolides, iriomoteolodes-14a and 14b, from the marine dinoflagellate Amphidinium
species collected off Iriomote Island, Okinawa. The structures including the
absolute stereochemistry of eight stereocenters were determined on basis of
spectroscopic data and chemical conversion method. These compounds are
analogous to known macrolides, amphidinolides O and P, and the biosynthetic
relationships for four compounds are also described.
Quantitative nuclear magnetic resonance is
a powerful tool in quantitative determination of the main component and
impurities in a drug substance or a drug product because of its high accuracy,
precision and efficiency. This method has the potential to establish
metrological traceability easily and expected to be widely utilized for some compendial guidelines and official
standards. In this study, the authors conducted
an inter-laboratory comparison for qNMR methodology and confirmed that statistically
qNMR has the competence to obtain the same quantification performance and
accuracy as the conventional reliable methods.
Tyrosyl radical
generation plays a major role in hemin/peroxide-induced oxidative stress. The authors developed a
method for trapping tyrosyl radicals using a derivative of N-methyl
luminol, a tyrosine labeling reagent. The
derivative selectively forms a covalent bond with tyrosine residue (tyrosine
click reaction) under single-electron oxidation conditions. This reaction
labels oxidative stress hotspots not only at the protein level but also at the
level of tyrosine residues undergoing oxidation. The cover picture depicts
an image of tyrosine click reaction to aid in the visualization of
hemin/peroxide-induced oxidative stress generated in blood vessels.
Amine
groups occur widely in many naturally abundant chemicals and artificial functional
molecules. Efficient C–N bond conversion methods suitable for late-stage
functionalization would greatly expand their synthetic utility. However,
transformation of C–N bond is generally difficult, due to the high stability. Ammonium salt is an ideal pre-activation form for
amine, since it can be obtained quantitatively from amine via simple protocol.
In this review, synthetic transformations through ammonium C–N bond cleavage developed by the author’s group are
summarised, describing a new trend for utilization of amine in organic
synthesis.
The authors previously reported
novel β-galactosidase activity in the human Golgi apparatus and predicted the precursor
GLB1 isoform 1 as the enzyme responsible for this activity. GLB1
isoform 1 is involved in lysosomal storage diseases and widely used as a
biomarker of cellular senescence. Inhibitor-derived chemical probes may serve as powerful
tools for identifying the enzyme. In this study, the authors screened
inhibitors from two compound libraries. One of the
obtained inhibitors showed increased inhibitory activity following redesigning
using molecular docking simulations. This inhibitor may
be useful for developing chemical probes to identify the enzyme discovered
by the authors.
Honey produced from manuka in New Zealand
has exceptionally high antibacterial activity and is approved as a medicine for
wound care. In this paper, authors developed a simple and rapid evaluation
method for the antibacterial activity of manuka honey by using a fluorescence
fingerprint (excitation and emission matrix). Three distinct wavelength
combinations of fluorescence were obtained from the honey samples. A
correlation between the fingerprint and the antibacterial activity was
indicated by a multivariate analysis, and authors succeeded in the evaluation
of the activity from the fingerprint. Furthermore, some chemicals (leptosperin
and leptosperin) were indicated as antibacterial compounds in the honey.
There are a lot of medicines having anticholinergic actions as side
effect. However, it is sometimes difficult to examine side effect only in
clinical studies because of various limitations. Therefore, the authors tried
to predict anticholinergic activity on the basis of compound’s structures by quantitative structure-activity relationship (QSAR) and docking study. These methods might be
helpful for risk assessment of anticholinergic side effects.
Because
of the complexity of nanomedicines, analysis of their morphology and size has
attracted considerable attention. The atomic force microscope (AFM) has emerged as a
powerful tool for providing detailed morphological characteristics of
nanoparticles. To assess the applicability of standardization of AFM as
an analytical methodology of nanomedicines, in this study, authors identified robust
conditions for assessing the morphology and size of nanoparticles based on a
polystyrene nanoparticle certified reference material standard. Under the
optimized conditions, there were no significant inter-instrument differences in
the analyzed size values of polystyrene nanoparticles both in air and under
aqueous conditions.
This paper
analyzes and summarizes the
development of novel drug formulations in order to optimize targeted drug
delivery in the treatment of bone metastasis using bone-targeting ligands and
antibodies to metastatic cancer. Metastases of the bone is a common development
especially in patients with breast and prostate cancers. However, most drugs
are inefficiently distributed to the bone and are hence pharmacologically
suboptimal in treating metastases in the bone. This paper could be useful for
the development of drug targeting technologies for the treatment of bone
metastasis.
Because
brain disorders such as glioma, Alzheimer’s disease and Parkinson’s disease are
lethal, or cause severe symptoms, medical treatment is needed. Recently, with
the progress of understanding pathology, new therapeutic candidates have been
developed. However, there are still unmet medical needs in the medication of
brain disorder. This is mainly because most drugs cannot cross blood-brain barrier
(BBB). To solve this problem, drug delivery system (DDS) using some approaches
(e.g. antibody, nanocarrier, ultrasound irradiation) is being studied for
overcoming BBB. In this review, we comprehensively reviewed on the development
and therapeutic application of brain-targeted DDS.
Passive targeting can be applied to a
relatively wide range of cancer types due to the enhanced permeability and
retention (EPR) effect that is the basis of its theory. However, recent clinical
data indicate that the tumor accumulation is only approximately 10% of the
dose, and satisfactory results are most rarely obtained using only EPR effect
strategy. In this article, the authors introduce the strategy of enhancing the
EPR effect using S-nitrosated human serum albumin dimer (SNO-HSA Dimer) and the
DDS strategy utilizing the endogenous albumin transport (EAT) system of tumor
cells and its future development.
Inhaled lung
cancer therapy is promising because of direct and noninvasive drug delivery to
the lungs with low potential for severe systemic toxicity. In all clinical
trials with nebulization of chemotherapeutic drugs, however, there was no
obviously superior anticancer efficacy in lung cancer patients even at the
maximum doses of drugs limited by pulmonary toxicity. Thus the addition of further
drug delivery functions including sustained release, prolonged retention, and
targeting in the lungs has been strongly desired to achieve enhanced anticancer
efficacy and attenuated pulmonary toxicity of inhaled chemotherapeutic drugs
and other drug candidates.
Combination therapies using
multiple drugs are the effective strategies to treat tumors. Various
therapeutic regimens have been developed. Here, co-delivery of multiple drugs
to tumor tissues using nanotechnology is theoretically useful to improve the efficacy
and safety of the regimens. In this review, the authors summarized the current
state of co-delivery systems of multiple drugs, including small-molecular
chemotherapeutic drugs, proteins, nucleic acids and gene medicines. Especially,
they pointed out the importance of selection of the combination, targeted
delivery of multiple drugs, and controlled release of drugs based on
environment-responsive mechanisms. Co-delivery systems are the promising
approach even for immunotherapy using checkpoint inhibitors.
Introduction of a fluorofunctional group into
organic compounds has been an important topic in the pharmaceutical science
field. Although various types of fluorofunctionalizations have been actively
investigated so far, applicable substrates are still limited and the
development of a new methodology for the preparation of new materials having
fluorofunctional groups is in high demand. In this personal account, 1)
trifluoromethylations of C–C multiple bonds, 2) asymmetric
fluorofunctionalizations of alkenes, and 3) C–H fluorofunctionalizations, which
have been reported by the author and co-workers, are described.
Myostatin is a negative regulator of skeletal muscle
growth. Recently, the authors developed 16-mer peptidic myostatin inhibitor
MIPE-1686, which enhances muscle mass and grip strength in mice. The present
study demonstrates that a linear peptide MIPE-1686 with N-terminal unprotected
is amazingly stable against recombinant human proteases (aminopeptidase N,
etc.). This implies that MIPE-1686 has a potential to act long-lasting in
vivo. The results also suggest that the secondary structure of a relatively
small linear peptide may influence the recognition by degradation enzymes. This
would give a valuable information for designing a stable linear peptide drug in
vivo.
One of the oldest dye plants, Mercurialis leiocarpa
(Euphorbiaceae), had been used as a blue dye until indigo dye
appeared in Japan. The constituents are expected the application as medicines.
In this paper, the authors isolated a new nitrogen-containing asymmetric
dimer, leiocarpanine A, from the aerial parts of this plant and described the chemical
elucidation, the estimation of the generation process, and the concise
synthesis by
mimicking the generation process through radical intermediates. This synthetic method provides
a rapid and concise pathway to construct a library of nitrogen-containing
dimers that might be useful for drug discovery.
Inhibitors of human β-N-acetyl-D-hexosaminidase A,
hHEXA, have the potential to a pharmacological chaperone for Sandhoff disease
and Tay-Sachs disease as lysosomal storage diseases. The hHEXA inhibitors have
been shown to successfully enhance hHEXA levels, leading to the chronic form of
these diseases. To develop hHEXA inhibitors, authors analyzed the hHEXA active site
structure and designed the specific hHEXA fluorogenic substrates based on the
authors’ substrate design platform. The designed substrates were synthesized
and these were exhibited excellent specificity and sensitivity for hHEXA in
three human cell lines. These are all new substrates that can be utilized to
screen hHEXA inhibitors in human cells.
There is a great need for reagents
that are environmentally benign, easy to
handle, inexpensive, and safe in organic synthesis. In this context, the authors have developed hydrophilic
polyacrylamide-gel based triazine-type condensing reagents, PAG-Trz-Cls, which
were synthesized from inexpensive materials via radical polymerization. PAG-Trz-Cls
are non-hygroscopic solid, high-loading, well-swollen in water and alcohol.
Owing to these features, condensation between highly polar carboxylic acids and
amines in an aqueous solvent successfully proceeded, and purification of the
resulting amides can be readily carried out by filtration.