Molecular space chemistry is an important
concept for the design of novel functional materials and catalysts. The research group “Molecular space chemistry
for the chemical conversion” was established by the member who advocate that the organic integration of
supramolecular chemistry and catalytic chemistry enables flexible chemical
conversion in multi-component molecular ensembles. It is noteworthy that most of the member got
a position of full professor (or similar position) in these few years. To this volume of Chem. Pharm. Bull., four of
the members, who have deep connection with the Pharmaceutical Society of Japan,
contribute their cutting-edge results.
This report
describes the synthesis of novel dual-purpose reagents, p-methoxybenzyl N-acetylcarbamate
potassium salt (PM-BENAC-K) and 2,4-dimethoxybenzyl N-acetylcarbamate
potassium salt (2,4-DM-BENAC-K). The BENAC-Ks were stable colorless powders
synthesized via a simple three-step procedure without column chromatography, which
can be easily scaled-up. The BENAC-Ks reacted with various alkyl halides and
sulfonates to form substituted products that were converted to N-alkylacetamides
via acid-mediated deprotection. Simultaneously, p-methoxybenzyl and 2,4-dimethoxybenzyl
carbamates were obtained via base-mediated deacetylation. Thus, the BENAC-Ks are
worth remembering as simple reagents for synthesis of acetamides and benzyl
carbamates.
Mitragyna
speciosa,
which belongs to the Rubiaceae family, contains several corynantheine-type
monoterpenoid indole alkaloids that exhibit potent biological activity,
including analgesic activity. In this article, the authors reported the
asymmetric total syntheses of such Mitragyna alkaloids mitragynine,
speciogynine, and 7-hydroxymitragynine. These syntheses were accomplished via asymmetric
organocatalytic Michael reaction, diastereoselective Pictet-Spengler
cyclization, and biogenetically inspired chemical transformations within 12
steps and in >11% overall yield from commercially available materials. These
syntheses will strongly promote the
structure-activity relationship study of Mitragyna alkaloids.
Biomembranes constitute the boundary
between the living organism and the external environment, and their function is
essential for maintaining biological activities. Quantitative understanding and
precise control of the transport and conversion of various substances across
biomembranes are important issues in biophysics and cell biology, but dealing
with biomembranes, which are multi-component, heterogeneous, and complex
systems, is not an easy task. In the Current Topics, investigators who are boldly
tackling this area of research introduce recent advances in biophysical and
molecular biological aspects and technology.
The
linear 1,3-diol structure is a common motif in
biologically active molecules. C-H functionalization at an α-position of alcohols
leads to efficient synthesis of sugars and polyols. However, regioselective
conversions at the alcohol α-position of linear 1,3-diols have been limited.
Nakao et al. developed secondary-alcohol-selective C-H alkylation of 1,3-butane
diol by combining an acridinium photoredox catalyst and a thiophosphoric acid
hydrogen atom transfer (HAT) catalyst. The use of DCM as a solvent with a
relatively small dipole moment improved secondary α-alkoxy C-H selectivity by
making the C-H abstraction process the rate-limiting step.
Hardness is a
critical quality characteristic of pharmaceutical oral jelly. The purpose of this
study is to determine the hardness using time-domain NMR (TD-NMR). After
measurement of the T2 relaxation curves of the test jellies
by TD-NMR, the acquired data were analyzed by partial least squares (PLS)
regression analysis. Eventually, an accurate and reliable PLS model was created
that enabled accurate assessment of the hardness of the test jellies. TD-NMR
enables the measurement of samples nondestructively and rapidly with low cost,
and so could be a promising method for evaluation of the hardness of
pharmaceutical oral jellies.
This paper describes
acid-mediated aryne generation from o-triazenylarylboronic acids. The
authors previously reported these practical aryne precursors generate arynes by
the treatment with silica gel. In this paper, they reported acids including Brønsted
acids, Lewis acids, and solid acids are also effective for aryne generation
from the precursors. In particular, the use of camphorsulfonic acid provided high
yields in reactions with a range of arynophiles, and enabled chemoselective reaction
with a furan in the presence of an amine. Hammett plot analyses revealed that
an aryne generation mechanism induced by the acid is distinct from the
mechanism induced by silica gel.
The ligand-binding
sites of F1*S and A variants of human α-acid glycoprotein (hAGP), and chicken AGP were completely
different. The former sites were located in lobs I-III including W122, while
the later ones were located near W26. Both (R)- and (S)-benzoin
were docked onto a cavity of the generated model structure of cAGP. In addition
to hydrophobic interactions, some of hydrogen bonding interactions worked for
chiral recognition of (R)-
and (S)-benzoin. (R)-Benzoin
bound to cAGP more tightly than (S)-benzoin. The elution order of benzoin enantiomers on
chiral stationary phases based on cAGP in LC were consistent with the docking
results.
Due to
the importance of chemical modification of RNA, methods for chemical modification
at a predetermined site in an internal position of RNA have attracted much
attention. The authors have developed an original method for the base- and
sequence-specific modification by transferring the functional group of the oligonucleotides
to RNA through the formation of hybrid complexes. To achieve further
modification by copper-catalyzed alkyne-azide cycloadditions, the authors
investigated transfer groups with the tri-, tetra- and pentaethylene
glycol-linked alkynes. As a result, the transfer groups with tetra- and
pentaethylene linkers were determined to be promising compounds to internally modify
long RNA.
This paper reports the successful use of a cationic liposomal-encapsulated
novel 13-substituted berberine derivative for the targeted cell uptake and
delivery to the cancer cell nucleus. Additionally the liposome also assists
with stabilization of the selectively toxic anticancer berberine derivative
with respect to oxidative cleavage in solution. Liposomes derived from a cholesterol-based
lipid with a polar side chain which would become cationic after amine
protonation, were of particular interest. Enhanced cancer cell toxicity was
seen in vitro with the cationic liposomal
formulation of the berberine derivative possibly via inhibitory interactions
with the cell’s telomere/telomerase system.
This paper describes a
stereoselective synthesis of a cis-fused 5,6-ring skeleton in
picrotoxane-type sesquiterpenes. This bicyclic skeleton is a synthetic
challenging structure because of the presence of multiple consecutive
stereocenters including two tetrasubstituted carbons at the angular positions. The
authors developed a synthetic method of the core structure via DL-proline-mediated
intramolecular aldol reaction accompanied
with the desymmetrization of the 2-methyl-1,3-cyclopentanedione moiety
and the construction of four contiguous
stereocenters. This reaction can be also applied to the kinetic
resolution using L-proline, implying that the established method would be
useful for the synthesis of natural products classified as picrotoxane-type
sesquiterpenes.
Many
drugs being used in chemotherapy of cancer has nitrogen-containing heterocyclic
moieties as their basic structure, and the authors extensively focused on the
1,3,4-oxadiazole and benzimidazole scaffolds. In this article, two series of novel
hybrids combining the 1,2-disubstituted benzimidazole and 1,3,4-oxadiazole or
thioether linked 1,3,4-oxadiazole were designed and successfully synthesized.
The in vitro cytotoxicity bioassays came up with the discovery of three
lead compounds which displayed 4.5-13 fold increase in activity compared to
5-FU against the three human cancer cell lines (HeLa, MCF-7, A549), meriting
further characterization and serving as promising scaffolds in the discovery of
new potent anticancer agents.
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.
Particle
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.
The highly
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
formulation study.
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.
This
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
Maxim.,
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
activity.
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.