The authors had held a symposium, “New modalities
and strategies in drug delivery and discovery”, in the 36th Annual Meeting of
the Academy of Pharmaceutical Science and Technology, Japan (APSTJ) in
Tokushima (online), Japan, 2021. In the symposium, the active young researchers
from the Graduate School of Biomedical Sciences of Tokushima University presented
various topics on their own researches. This Current Topics accumulated the review
articles from the invited speakers of the symposium. These reviews will provide
a wide range of intimate information regarding new modalities and strategies in
drug delivery and discovery.
size-monitoring method using a handheld-type Raman spectrometer is proposed in
this study. Two types of fine particles with the same formulation under
different operating conditions were prepared for calibration purposes. There was
a relationship between particle size and Raman intensity during processing and
calibration curves could be obtained in both operating conditions. Two other
types of fine particles with the same formulation, but on different scales or
using different processing mechanisms were also prepared for verification
purposes. The particle size could be successfully predicted using the
calibration curve obtained taking powder porosity into consideration.
The authors elucidated the mechanism of solubilization
of poorly water-soluble drugs using zeolitic imidazolate frameworks (ZIFs), a member of metal-organic
frameworks. The solubility of ZIF-trapped drugs was enhanced compared to the
raw drugs. The authors focused on 2-methylimidazole (2-MIM), used as an organic ligand in ZIFs. Drugs were
easily dissolved by the addition of 2-MIM, suggesting that the
presence of 2-MIM enhanced the drug solubility. The findings of this study demonstrated the
solubilization mechanism of poorly water-soluble drugs using ZIFs. ZIFs are expected to be used as drug carriers to maximize the
bioavailability of poorly water-soluble drugs.
enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C1-symmetric
biaryl compounds including heterocyclic moieties, such as carbazole and
dibenzofuran, has been achieved for the first time. This enzymatic esterification
was accelerated by the addition of disodium carbonate while maintaining its
high enantioselectivities (up to 99% ee), and was particularly effective for
biaryls having N-substituted carbazole moieties. Furthermore, mesoporous
silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of
3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in
one-pot to synthesize the optically active heterocyclic biaryl compounds with
high optical purity.
Biopharmaceutical dry powder inhaler
(Bio-DPI) is an attractive formulation for non-invasive administration method
for biopharmaceutical compounds. In Bio-DPI to ensure spray stability, it is
important to control the powder caking risk of the formulation. To detect
powder caking risk, Void Forming Index (VFI) is a useful method for DPI
The authors conducted formulation screening
using VFI, to develop a high-dose Bio-DPI formulation containing 50 mg of
lysozyme per capsule. As a result, VFI clarified the powder caking risk of each
formulations and contributed to selection of high spray stability formulation.
paper describes the synthesis of new derivatives of habiterpenol and their structure-activity
relationships. Habiterpenol is a G2 checkpoint inhibitor that has recently
attracted attention as a new vital molecular-targeting therapeutic agent. Combination
therapy using low-doses of anticancer agents and G2 checkpoint inhibitors has
great potential as an effective treatment for cancer because it minimizes the
dosage of the DNA-damaging anticancer agents and results in fewer side effects.
The authors have independently developed a total synthesis to obtain new habiterpenol
derivatives that cannot be derived from natural products, and have further
studied their structure-activity relationships.
This paper reports one rare azapyrene alkaloid named caulophyine A along with six known compounds identified
from the roots of Caulophyllum robustum
which was collected on Taibai mountain, the highest peak of the Qinling
mountains, Shaanxi province, China. Caulophyine A is a nitrogen containing polycyclic aromatic
hydrocarbon, possess a naphtho[2,1,8-def]isoquinoline
fragment. This is the first
report of the nitrogen containing azapyrene alkaloid identified from plant. The
in vitro bioassays revealed that caulophyine A displayed weak acetylcholinesterase (AChE) inhibitory
The authors successfully demonstrated that expression of a hCYP
gene in a filamentous fungus led to the identification of a bioactive natural
product from a strain previously not reported to produce the compound, and a
prodrug-like secondary metabolite that can be activated by an hCYP. Our
approach can be further developed by employing other types of CYPs and
prodrug-activating enzymes in combination with microbes, with differing
secondary metabolite biosynthetic potentials, to explore a wider biosynthetic
space for identification of interesting prodrug-type natural products.
The application of
mass spectrometry has been reevaluated in the field of pharmaceutical research.
The recent launch of the EchoMS system, which combines an MS/MS system with an acoustic
nano-liter dispensing system, has enabled label-free high-throughput screening
(HTS) assays for disease-related enzyme reactions without time-consuming chromatographic
separation. As the search for therapeutic agents for COVID-19 is currently
underway, the authors conducted an HTS campaign for SARS-CoV-2 3CL protease using
this system. A library of 32,033 compounds was assayed in 12 hours, and several
inhibitors with antiviral activity were found in further cell-based assay.
Pathogenic scrapie PrP
(PrPSc) accumulates in the brain resulting in the prion disease
progression. SPECT imaging of PrPSc could non-invasively diagnose prion
disease. The authors developed novel radioiodinated styryl chromone (SC) and
vinyl pyridyl chromone (VPC) derivatives for PrPSc imaging. They
found that the SC derivatives possess affinity for PrPSc, while the
conversion to the VPC derivatives abolishes the affinity. These results
indicate that a single aromatic ring in the imaging agents can make a
significant difference in the recognition of PrPSc. [125I]SC-NHEtOH
was shown to be a potential scaffold for the further development of prion imaging
Because 40% of the world’s population is faced with
the risk of Dengue virus (DENV) infection and no drug has yet been approved,
development of an anti-DENV agent is a key priority for human health. In this
article, the authors revealed that a combination of 4’-thio-modification and
introduction of monophosphate prodrug skeleton to nucleoside analog, for
example 5-ethynyl-(1-b-D-ribofuranosyl)imidazole-4-carboxamide (EICAR), is
valuable tactic to develop an effective anti-DENV agent.
The authors designed and synthesized two
visible light-absorbing hypervalent iodines, and investigated their property of
photo-reaction. Since heavy atom-containing molecules cause a direct triplet
excitation, these molecules promoted photo-oxidation under the irradiation of wavelength
exceeding their singlet excitation region. The various photo-oxidations are
demonstrated: oxidation of primary and secondary alcohols, diol, and sulfoxide.
Furthermore, spectroscopic analysis including phosphorescence excitation, and density
functional theory calculations were performed to prove the reaction mechanism
of the photo-oxidation in detail.
In this review, the author summarized his protein
modification studies over the past decade. By utilizing highly reactive
chemical species such as radical species and singlet oxygen, the author has
developed novel methods for the selective modification of tyrosine and
histidine residues, which have been difficult to be modified by conventional
methods. In addition, The author took advantage of the high reactivity of these
active species to apply protein modification reactions that proceed selectively
in the space of a few nanometers around the catalyst.
Surface plasmon resonance (SPR) sensors have been widely applied in various
fields of biotechnology and pharmacology, including drug discovery, biomarker
screening, virus detection, and food safety testing. In this report, a
metal-insulator-metal (MIM) type SPR sensor was fabricated by placing an
insulator layer on top of a gold thin film and then arranging gold colloidal
particles in a two-dimensional regular array on the insulator layer. Because of
resonance of the plasmons of the gold particles and the thin film, multiple
plasmon peaks/dips were observed. The substrate was shown to have twice the
sensing capability of the gold particles.
United Nations’ Sustainable Development Goals (SDGs) provide guidelines for
achieving a better and more sustainable future. Small-molecular drugs contribute
to SDG3 (“Ensure healthy lives and promote well-being for all at all ages”), and
waste reduction in small-molecular drug syntheses contributes to SDG6 (“Ensure
availability and sustainable management of water and sanitation for all”) . The
authors described an environmentally friendly scaled-up synthetic method for retinoid
X receptor agonist NEt-3IB, a candidate for treating inflammatory bowel
disease, by employing a reusable hydrophobic ether and ethanol.
polysaccharides (EPSs) are carbohydrate polymers secreted by bacteria, fungi and algae, and have various biological activities. EPSs from Leuconostoc mesenteroides subsp. mesenteroides strain NTM048 (NTM048 EPS) enhance IgA production of
mouse. In this study, the authors developed efficient synthetic routes to the
NTM048 EPS fragments and evaluated their effects on IgA-inducing activity. The
synthetic fragments showed a slight IgA-inducing activity, but the levels were not
as high as those of the NTM048 EPS, revealing that the activity by EPS might be
associated with the recognition of larger fragments or whole glucans, rather
than the recognition of glycan substructures.
The authors have isolated a new pentacyclic monoterpenoid indole
alkaloid glycoside, named secorubenine, from the heartwood of Adina rubescens,
a plant used as a traditional medicine in Southeast Asia. Its structure was
determined by careful analysis of the collected NMR spectra and chemical
modification of the isolated natural product. Furthermore, the enantioselective
total synthesis of secorbenine was immediately achieved by applying the
bioinspired total synthesis of monoterpenoid indole alkaloid glycosides
previously established by the authors. Thus, the exact structure of
secorubenine, including absolute stereochemistry, was confirmed.
A combination of biophysical techniques revealed various complex molecular interactions in membranes. Antimicrobial peptides form toroidal pores with surrounding lipids, followed by translocation into the cytosol. Amyloid β-protein recognizes clusters of monosialoganglioside GM1 on neuronal membranes, forming toxic amyloid fibrils containing 2-residue-shifted antiparallel β-sheets. The coiled–coil labeling method enables a quantitative analysis of membrane protein associations. The introduction of a GXXXG motif drives the formation of an otherwise unfavorable parallel dimer of a model transmembrane helix.
These current topics introduce the latest research on the liquid
chromatographic techniques utilized in food analysis. These liquid
chromatographic techniques are based on various detection methods including UV detection,
fluorescence detection, electrochemical detection and MS. These methods
incorporate innovations that go beyond simple chromatography, such as
derivatization to improve detectability of analyte, effective separation from
matrices by fluorous chemistry, multidimensional chromatography to separate a
wide range of polar compounds, and the use of methylated reference for the
determination without calibration curves using single reference liquid
chromatography. The contents of the topics would provide useful suggestions to improve
analysis of important ingredients in food samples.
The overestimation of osmium
is often observed in spike recovery test by ICP-MS. This is because osmium
formed the highly volatile osmium tetroxide in an oxidation reaction when microwave
digestion. The authors investigated the methods to stabilize osmium by using four
compounds, thiourea, ascorbic acid, sodium sulfite, and potassium
metabisulfite, that could reduce the overestimation of osmium isotopes. All
compounds were useful for stabilizing osmium and showed good spike recovery
results. The influence of adding compounds against other elements defined by
Q3D was also investigated.