To enhance the structural diversity in aryne-based products, the aryne precursors bearing various functional groups have been continuously
developed. However, the use of unsymmetrically substituted
arynes is frequency constrained by the low regioselectivity.
Authors achieved
the regiocontrol by introducing
a fluoro-substituent in unsymmetrically 3,6-disubstituted arynes as a directing group. Particularly, the use of 3,6-disubstituted aryne having fluorine and bromine atoms led
to the good degree of regiocontrol in several reactions. These results consist with aryne distortion models reported by Garg and
Houk’s group.
A chiral lithium binaphtholate
base catalyst effectively mediates the asymmetric Michael addition of ketones
to less reactive acrylamides in a highly enantioselective manner. A small
excess of lithium tert-butoxide relative to the binaphthol is used to
facilitate the enolization of the ketone, thereby improving conversion of the
asymmetric Michael reaction. Computational studies support that the 3- and
3'-phenyl groups of the binaphtholate catalyst control the orientation of the
lithium enolate and the subsequent approach of acrylamide to achieve high
enantioselectivity.
This
study evaluated the effects of different forms of granulated lactose (GL) on
the physical properties of tablets and the effect of magnesium stearate on each
type of GL. The different forms of GL such as agitated granulation (GL-AG),
spray-dried granulation (GL-SD), and fluidized bed granulation (GL-FB) were
added as excipients during direct powder compression. When tablets with the
same blending conditions were compared, the tensile strength and disintegration
time followed the order as GL-FB > GL-SD > GL-AG. The authors presented
selection criteria for the suitability of different forms of GL during
tableting by examining the relevance between the type of GL and properties of
the tablets produced.
Readthrough
therapy, which restores the biosynthesis of full-length proteins by incorporating
an amino acid at a premature termination codon and allowing translation to
continue, has recently been actively investigated for its application to nonsense
mutation-related diseases. In this article, triaryl derivatives were
synthesized and evaluated for the development of novel readthrough agents to
treat mucopolysaccharidosis type I, which is caused by nonsense mutations in
the IDUA gene. KY-516, a representative compound, exhibited excellent
readthrough-inducing activity in the luciferase assay and significantly
increased enzyme activity in mutant IDUA transgenic cells.
In this Article, the authors investigated the effects of
fluorine atoms introduced to the terminal positions of the side chain (26 and 27-positions)
of 25-hydroxyvitamin D3 (25(OH)D3) on vitamin D receptor
(VDR) binding affinity, osteocalcin promoter transactivation activity, and levels
of resistance against CYP24A1-dependant metabolism. They revealed that these
biological activities were enhanced in the order of 26,27-difluoro,
26,26,27,27-tetrafluoro, and 26,26,26,27,27,27-hexafluoro-25(OH)D3. Introduction
of fluorines at these positions lead to improvements on functions as VDR-ligands
and biological activity. With regard to the VDR binding affinity, the authors
considered those potency improvements might be attributed to the increased acidity
of the 25-OH group.
The authors synthesized jadomycins and their
structural analogues, evaluated their cytotoxic activity, and addressed
structure-activity relationship study of jadomycins. They achieved the total
synthesis of jadomycin T and jadomycin aglycons using L-threonine and
1-amino-2-propanol as nitrogen sources. When the cytotoxicity of jadomycins were
evaluated in several tumor cells, the jadomycin aglycons tended to be more
cytotoxic than the jadomycins. The authors also demonstrated the potential
application of jadomycins as lead compounds for the treatment of brain tumors.
This paper provides important insights into the total synthesis of other natural
organic compounds, structure-activity relationship studies, and development of
new therapeutic drugs.
To develop dearomatization reactions based on a
nucleophilic activation of phenols, naphthols, and indoles, ipso-Friedel–Crafts-type
C-alkylation must be selectively promoted over competitive O- or N-alkylation
reactions. Resolving this chemoselectivity issue is essential for developing
this class dearomatization reaction. Author’s research group found that various
dearomatization reactions could be developed using appropriately designed aromatic
substrates with an electrophilic moiety for intramolecular reactions. This
review describes dearomatization reactions using Pd catalysis, Au catalysis,
and Ag catalysis, which provided access to a wide variety of dearomatized
products from planar aromatic compounds in a highly chemoselective manner.
Aryl
hydrocarbon receptor (AhR) is known to be related to the metabolic pathway of
xenobiotics but recent studies revealed that AhR is also associated with the life
cycle of the virus and inflammatory reactions. In this article, the authors
screened a natural product library and identified methylsulochrin as a partial
agonist of AhR. Methylsulochrin exhibited antiviral activity against the hepatitis
C virus and suppressed the production of an inflammatory cytokine, interleukin-6,
in macrophages. These results suggested the possibility of methylsulochrin derivatives
as anti-hepatitis C virus compounds with anti-inflammatory activity.
Two topics on novel synthetic strategy are
shown. The first topic concerns enolate chemistry. The enolate structure has
been long believed to be achiral because all
four substituents are in the same enolate plane. From the viewpoint of dynamic
chirality, however, the enolate can exist as an axially chiral form or a planar
chiral form in a limited time scale. The author demonstrated that these chiral enolates
can be employed as reliable intermediates for asymmetric synthesis. The second topic
concerns catalyst function. 4-pyrrolidinopyridine (PPY) had been known to be
the most active catalyst for acylation. Based on the PPY skeleton, strategies for enantio-
and site-selective catalysis were proposed. The latter opened up a new way to total
syntheses of natural glycosides in extremely short overall steps.
This “Current Topics” contains one review
and four regular articles describing the latest research on natural product
chemistry that have been contributed by young researchers. These contents include
computer science technology in natural products research, isolation of biological
constituents from medicinal plants, evaluation of the biological activity of
natural products, and synthesis of biological constituents from medicinal
plants. These
findings could be useful for the development of effective medicines from natural
medicinal resources.
The hydration behavior of hydrophilic
matrix tablets is a crucial process for the in vitro release of highly
water-soluble drugs. This article presented a novel method for continuous
monitoring of the hydration behavior by using time-domain nuclear magnetic
resonance (TD-NMR). TD-NMR has an ability to identify the NMR signals
corresponding to the nongelated core remaining in the sample from the measured
T2 relaxation curves. The authors succeeded in characterizing fully the
hydration behaviors of the model matrix tablets. The TD-NMR method is powerful
to evaluate the hydration properties of hydrophilic matrix tablets.
The authors have reported various derivatives
of lysophosphatidylserine (LysoPS) as potent and selective agonists for each
LysoPS receptor subtype. In order to further develop these LysoPS analogs to
drug candidates, appropriate pharmacokinetic consideration is essential. They
found that the ester bond of LysoPS is highly susceptible to metabolic
degradation in mouse blood and examined isosteric replacement of the ester
linkage with heteroaromatic rings. The resulting compounds showed excellent
retention of potency and receptor subtype selectivity, as well as increased
metabolic stability. This work provides a molecular basis for the
design of phospholipid-based agonists with improved metabolic stability.
In peptide drug discovery, it is important
to develop efficient synthetic methodologies to access cyclic disulfide
peptides with the expression of functional activity and resistance to metabolic
enzymes. In this study, the authors developed a one-pot disulfide-driven cyclic
peptide synthesis. The entire process is carried out using solid phase peptide
synthesis, thus eliminating complicated work up procedures to remove
by-products and enabling production of high-purity cyclic peptides by simple
cleavage of a peptidyl resin. Consequently, the one-pot synthesis of oxytocin as
a model cyclic disulfide peptide was successfully accomplished using this
method. Their study has contributed for the preparation of more complex and
artificial disulfide peptides.
Good
adherence to medication is critical for successfully treating psychiatric
disorders.
The
authors developed two types of aripiprazole gummies (ARP-Gs) with organoleptic
masking, cocoa- and fruit-flavoured ARP-Gs using a commercially available ARP
formulation. They evaluated the overall palatability and acceptability of the
ARP-Gs by
performing a gustatory sensation test in healthy volunteers. The both ARP-Gs exhibited
superior palatability, and greatly exceeded the cut-off values of
acceptability.
The
ARP-Gs could be alternative dosing forms in patients with schizophrenia, and
pharmacists can prepare these formulations in pharmacies to enhance medication
adherence and meet the specific needs of individual patients.
The authors have developed a series of
photoinduced-electron-transfer-driven (PeT-driven) nitric oxide (NO) releasers
that efficiently release NO upon irradiation with visible light. In this study
investigating the substituent effects at the 2-position of the
nitrosoaminophenol moiety, it was found that a methyl group had no significant
effect on NO-releasing ability, while a nitro or methoxy group reduced it. The
nitro group may suppress electron transfer to the antenna moiety, while the
methoxy group may accelerate electron transfer but suppress deprotonation of
nitrosoaminophenol. Understanding these structure-activity relationships could
aid in further functionalizing PeT-driven NO releasers.
The development of peptide bond formation
reaction enabling a convergent peptide fragment coupling is a major challenge
of recent years for synthetic chemists due to the rapidly growing interest in
the discovery of drugs base on the middle molecule peptides. The
decarboxylative amidation recently reported by authors’ group is a potential
solution to this problem. In this article, a mechanistic analysis and the further
development of the t-butyl hydroperoxide (TBHP) mediated-decarboxylative
amidation of α-ketoacids are described. A systematic examination and
understanding of the reaction mechanism enabled a modified epimerization-free
reaction whereby peptide fragment couplings using peptide α-ketoacids were
successfully achieved.
The
processed leaves of Hydrangea macrophylla Seringe var. thunbergii
Makino is listed as a Sweet Hydrangea Leaf (Hydrangeae Dulcis Folium) in the
18th edition of the Japanese Pharmacopoeia. The authors reported soils with pH
ranging from 7.0 to 5.5 was not only suitable for this plant growth but also
increased the content of phyllodulcin as sweetener in the leaves. In addition,
a correlation between the sweetness of the crude drug and phyllodulcin was shown.
These findings could be useful for the development of the crude drug with high-quality.
Oral disulfiram (DSF) has been used
clinically for alcohol dependence and recently has been found to have antitumor
activity. A transdermal delivery system would be useful for reducing the
frequency of administration of DSF for cancer treatment. The authors found that
the combination of oleic acid (OA) and Tween 80 further enhanced skin
permeation of DSF compared with individual application. The peak of CH2
asymmetric stretching vibration was blue-shifted by the application of OA, and
DSF solubility increased in response to Tween 80. Their study clarified the
detailed mechanism of action of skin permeation and promoting effect of DSF
through the combined use of OA and Tween 80.
This computational paper describes the
importance of treating electronic effects among hydrogen bond networks. Fragment
Molecular Orbital (FMO) method, which is a fast quantum-mechanics method, was
applied to the affinity prediction at the hydrogen bond networks of PDHK4. Authors
found that the FMO calculation with the solvation method of polarizable
continuum model (PCM) was important to increase the prediction accuracy. A
considerable amount of charge was transferred among the target site in the
FMO/PCM calculation, which was not described in the traditional
molecular-mechanics method. These results highlight the importance of electronic
effects in the affinity prediction toward hydrogen bond networks.
The
biowaiver scheme based on the biopharmaceutics classification system (BCS-BWS)
is used not only as terms of regulatory submissions but also as an indicator
for formulation development in drug discovery. The authors investigated the in
vitro dissolution rates of formulations of a BCS class III drug and compared
them with the criterion in the BCS-BWS. They also discussed the impact of
dissolution rates on bioequivalence for BCS class III drugs by virtual
simulation. These findings contribute to a better understanding of the biowaiver
approach and would help researchers in the formulation development of BCS class
III drugs.