In recent years, there has been significant
development of new drug modalities based on nucleic acids and peptides.
Consequently, there is a growing need to develop quality evaluation methods
suitable for the properties of medium-sized molecular drugs. In this research,
the authors focused on CD spectra to evaluate the secondary structure of
medium-sized drugs, aiming to develop testing methods based on modern
scientific standards, such as reducing the use of reagents and solvents. The
authors anticipate that the micro-sampling method developed in this study will
be applied as a quality evaluation method for medium-sized molecular drugs,
thereby contributing to the acceleration of their development.
Using the low-field NMR instrument, the authors continuously monitored the pseudopolymorphic transition from anhydrate to monohydrate. They chose ezetimibe as a model drug because of its characteristic chemical structure, i.e., the absence of methyl groups, and expected the difference in molecular mobility between anhydrate and monohydrate. The low-field NMR instrument was connected to a humidity controller, and the NMR relaxation was monitored, corresponding to a pseudopolymorphic transition. The used low-field NMR instrument has a permanent magnet and is easy to maintain; thus, this research may suggest its usefulness in controlling the quality of active pharmaceutical ingredient powders.
In this Note, the authors
reported the total synthesis of oxyphyllin A/belchinoid A, a
7,9-seco-8,12-dinor-guaiane sesquiterpene. The isolation of these compounds was
reported in 2023 by two independent groups. Chen et al. isolated oxyphyllin A
from the fruit of Alpinia oxyphylla Miq. and Yuan et al. isolated belchinoid A from the roots of Belamcanda chinensis. Both groups used NMR
spectroscopy and ECD calculations to determine the structure and their
conclusions were consistent, but the reported values of optical rotation
differed significantly. The authors synthesized these compounds using an
intermolecular alkylation/5-endo-tet sequential cyclization and
provided accurate spectral data and optical rotation.
Peptide
thioesters are important building blocks for the chemical synthesis of proteins,
and various methods for their preparation have been known. However, the preparation
of peptide thioesters containing sulfated-tyrosine is limited to a method using
a sulfate-protecting group strategy. The authors reported two methods for the preparation of
them without using a sulfate-protecting group. The first is based on direct
thioesterification on a protected peptide acid, and the other method is based
on thioesterification on an activated peptide azide. Two critical points are involved
in both methods: i) use of a counter-ion-stabilized sulfated-tyrosine, and ii) deprotection
of the protecting groups with TFA at low temperatures.
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The opioid µ receptor, which is the main target
of classical opioid analgesics, forms dimers with the opioid δ receptor. Targeting
this dimer is expected to have potent analgesic effects with fewer side effects,
although there are also counterarguments and ongoing debates. Herein, the
authors conducted a structure-activity relationship study of CYM51010, a µ/δ
heterodimer-preferring agonist, by dividing the molecule into three parts. The
findings obtained here will play an important role in developing selective
agonists for the heterodimer and elucidating its roles in both analgesic
processes and side effects formation.
In recent years, research on the natural
product biosynthesis using computational chemistry has been actively pursued,
leading to significant advancements in understanding complex biological
processes. This review provides an in-depth overview of a number of studies
conducted by the authors, focusing particularly on terpene compounds. These
studies not only contribute to the fundamental knowledge of natural product
biosynthesis but also hold potential applications in drug discovery,
agriculture, and biotechnology. The insights gained from these investigations
pave the way for future research in this rapidly evolving field.
Lipid
nanoparticles (LNPs) are crucial for mRNA medicine as they protect and deliver
mRNA into cells. The manufacturing process involves two steps: preparing LNPs
(upstream) and removing ethanol and exchanging buffers (downstream). Typically,
microfluidic devices and dialysis membranes are used for these processes.
However, determining the effects of manufacturing parameters on LNP quality is
challenging. Authors used extreme gradient boosting (XGBoost) to identify key
parameters such as ethanol concentration, buffer pH, and flow rate, which
impact particle size and encapsulation efficiency. Bayesian optimization was
then applied to derive conditions for manufacturing LNPs of varying sizes.
These findings will help improve the efficiency of mRNA-LNP manufacturing.
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Arginases I and II
are Mn(II)-dependent hydroxylases that
convert L-arginine into L-ornithine and urea in the urea cycle, and has been
proposed as a potential therapy target for various illnesses, such as
cardiovascular, anti-inflammatory, autoimmune, oncological, and infectious
diseases. Herein, authors report the isolations and structural
elucidations of three neo-clerodane diterpenoids, including two new
tinocordifoliols A and B and one known tinopanoid R from the Tinospora cordifolia stems as well as their
inhibitory activities against human arginase I. The assay revealed that tinopanoid R was a natural arginase I inhibitor
in a competitive manner with respect to L-arginine.
The
development of efficient synthesis of heterocyclic compounds is crucial
important for drug discovery. Authors have newly developed the oxidative
coupling of hydroquinones/4-aminophenols, bearing the electron-withdrawing
groups, with various olefins (styrenes, enol ethers, and allyl silane) to provide
dihydrobenzofurans as important heterocyclic skeletons for bioactive compounds
and natural products. For example, the oxidation of 2-methoxycarbonylhydroquinone
using 2,3-dichloro-5,6-dicyano-p-benzoquinone and the following coupling
with styrene in the presence of Lewis acidic FeCl3 could procced under
the mild reaction conditions to give the corresponding dihydrobenzofuran
product. This method can easily yield various dihydrobenzofurans that can contribute to drug discovery.
The authors achieved the first total
synthesis of silybin A, a hybrid natural polyphenol with attractive biological
activities. The
highlight of the study includes modified Julia-Kocienski olefination reaction
and Sharpless dihydroxylation, which enabled the highly stereocontrolled
synthesis. Additionally, the acid-promoted generation of two types of
quinomethide intermediates led to the biomimetic construction of both the
1,4-benzodioxane neolignane and the flavanol lignan core skeletons within
silybin A. The high generality of this methodology would allow for the
synthesis of a diverse array of structurally related silybins, isosilybins, and
other hybrid polyphenols.
Natural
products have played an important role in drug discovery. Recently,
pseudo-natural products, whose structures have been modified based on natural
products, have received much attention due to their unique biological
properties that differ from the parent compounds. This review describes a
series of total syntheses and structural elucidations of eurotiumides and
developments of pseudo-natural products carried out by the author concerning
the dihydroisocoumarin-type natural products eurotiumides with potent
biological activities. One-point chemical structural modification and the
dimerization strategy have led to the promising compounds, which are more
active than the parent natural product.
This
review describes the development of new synthetic methodologies for polyfunctional compounds using enamines and enamides carrying an oxygen atom
substituent on nitrogen atom, such as N-alkoxyenamines, N,2-dialkoxyenamines,
N-alkoxyenamides, and N-(benzoyloxy) enamides that have not received
much attention. The efficient
synthetic reactions using N-alkoxy-enamines and enamides as substrates proceed in
the presence of triarylaluminum reagent via cleavage of a relatively lower
energy N–O bond, and formation of new stronger bonds to afford 2-arylketones,
2-arylcarboxylic acids, tert-alkylamies carrying aryl group, 1,2-disubstituted phenethylamines,
and 2-amino-2-arylethanols that are useful as partial structures in
biologically active compounds.
The
solid-state properties of drug candidates are crucial for their selection
process. Traditional crystallographic techniques for structural analysis have
limitations and require high-quality single crystals. Microcrystal electron
diffraction (microED) can overcome these challenges by analyzing
difficult-to-crystallize or small-quantity samples. In this study, microED
rapidly determined the configuration of two crystal forms of the active pharmaceutical ingredient ranitidine hydrochloride. The structures obtained through
microED were consistent with those determined by X-ray crystallography,
demonstrating that microED is a valuable tool for efficiently elucidating molecular
structures in drug development and materials science
Authors
have developed heterologous expression technique applicable to huge
biosynthetic gene clusters (BGCs) which produce large molecular secondary
metabolites. Authors targeted
concanamycin BGC (~100 kb) in Streptomyces neyagawaensis IFO13477. Interestingly, heterologous expression of a
BAC clone of which insert size was 211 kb involving the entire concanamycin resulted
in the production of a new compound JBIR-157 in addition to concanamycin. INADEQUATE analysis revealed that JBIR-157
consists of an unusual new skeleton produced by the cryptic type-II polyketide
synthases (PKS) BGC. In this study, authors
reported the production, isolation, structure elucidation, and proposed
biosynthetic mechanism of JBIR-157.
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Significant efforts have focused on developing
cell-penetrating peptides (CPPs) for delivering nucleic acids into cells. In
this study, authors tested seven peptides for their effectiveness in delivering
plasmid DNA (pDNA). These peptides had previously been used for small
interfering RNA (siRNA) delivery, with one peptide containing the
dipropylglycine showing successful delivery with low cytotoxicity. Despite both
being nucleic acids, pDNA and siRNA differ in size and function, potentially
affecting optimal peptide sequences for delivery. The authors' results show
that three peptides were effective in pDNA transfection, with only one also
showing efficient siRNA delivery. These findings support our hypothesis and
provide insights for designing CPPs for both pDNA and siRNA delivery.
Preparation of drug metabolites at the milligram scale is essential for determining their structure and toxicity. However, their preparation using recombinant proteins and human liver microsomes is often difficult because of technical and ethical issues. In this study, authors found that bacteria isolated from “natto” can produce an unknown lidocaine metabolite, which is produced by human liver microsome. Then, they prepared a fraction containing the metabolite through mass cultivation of Bacillus subtilis, then identified the metabolite by NMR. Authors demonstrated that food microorganisms can be a tool to prepare drug metabolites at a low cost and without ethical issues.
This review describes the development of methodologies toward the unified synthesis of ellagitannins, a class of polyphenols with divergent structures, as reported by the Yamada group at Kwansei Gakuin University during 2017–2023. Efficient methods for constructing 3,6-O-(aR)- and 4,6-O-(aR)-hexahydroxydiphenoyl-bridged glucose moieties, in addition to various C–O digallate structures, are disclosed. The total synthesis of corilagin, mallotusinin, neostrictinin, and rugosin C is also achieved via application of the established methods, which are expected to enable increase of the number of ellagitannins that can be chemically synthesized.
The authors previously disclosed two synthetic routes to batrachotoxin, a potent cardio- and neurotoxic steroid isolated from certain species of frogs. The manuscript reports the attempted assembly of its ABCD-ring by an alternative strategy. While Pd/Ni-promoted Weix coupling linked the AB-ring and D-ring fragments, samarium(II) iodide-mediated pinacol coupling did not cyclize the C-ring. Instead, samarium(II) iodide promoted a 1,4-addition of the α-alkoxy radical intermediate to produce the unusual 11(9→7)-abeo-steroid skeleton. Thus, this study demonstrates the convergent assembly of the skeleton of the natural product matsutakone in 11 steps from commercially available 2-allyl-3-hydroxycyclopent-2-en-1-one.
This study provided the prediction equation of tablet strength of binary powder mixture with different plastic deformability. The five materials from the general pharmaceutical powders were selected based on their plastic deformability, and their compression properties were evaluated by the Heckel analysis and the compression energy analysis. The plastic deformability of the powder mixture was evaluated to estimate the tablet strength using the compression properties of powder mixture. This finding indicated that the ideal mass fraction of plastic powders to form tablets with sufficient tablet strength could be predicted from the compression properties of single material.
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N-H bond insertion reaction is
one of the useful transformations, wherein C1 units such as carbenes,
carbenoids, and their surrogates can be incorporated into N-H bond to form N-C-H bond. To achieve successful this
reaction, the use of diazo compounds as well as transition metal catalysts,
thermal conditions, or blue LED irradiation were often required. The authors
report a diazo- and metal-free N-H bond insertion
reaction of a hydrazone with alpha-keto ester, demonstrating a broad substrate
scope, a good functional group tolerance, and a late-stage functionalization of
pharmaceuticals.