In drug development, drug delivery into
brain across the blood-brain barrier (BBB) is a serious problem. Particularly, the
BBB is impermeable to large and medium-sized molecules. Accordingly, drugs for
diseases of the central nervous system (CNS) are unable to elicit their
activity in brain. However, receptor-mediated transcytosis can solve such
impermeability. Actually, using receptors such as transferrin receptor (TfR),
low-density lipoprotein receptor (LDLR), and insulin receptor (InsR), that
express on the surface of brain capillary endothelial cells, delivered well-designed
drugs into brain through endocytosis and exocytosis. This methodology will be a
promising approach to cure patients suffering from CNS diseases.
An efficient synthetic method for 2,5-disubstituted
tetrazoles from 5-substituted tetrazoles is developed. In this paper, the
authors established a cobalt-catalyzed site-selective alkylation of tetrazoles
via atom-economic hydroamination reaction between tetrazoles and non-activated
olefins. The authors also applied the developed reaction to an asymmetric
intermolecular hydroamination of non-activated olefins, which is one of the
longstanding problems in synthetic organic chemistry.
This
report describes the design, synthesis, and evaluation of a
new series of pyrazolo[1,5-a]pyrimidine derivatives for treatment against respiratory syncytial virus (RSV).
The pyrazolo[1,5-a]pyrimidine series of compounds containing a piperidine ring
at the 2-position of the pyrazolo[1,5-a]pyrimidine scaffold are known as
candidate RSV fusion (F) protein inhibitor drugs. The piperidine ring has been
revealed to facilitate the formation of an appropriate dihedral angle between
the pyrazolo[1,5-a]pyrimidine scaffold and the plane of the amide bond for
exertion of anti-RSV activity. A molecular-dynamic study on pyrazolo[1,5-a]pyrimidine
derivatives focusing
on the dihedral angles proposed and demonstrated potent anti-RSV inhibitors with
an acyclic chain instead of a piperidine ring. A subsequent optimization study on
pyrazolo[1,5-a]pyrimidine
derivatives containing
1-methylaminopropyl group led to a highly potent anti-RSV agent with an EC50
value of less than 1 nM.
Aphids have unique polyketide pigments, which possess
interesting biological activities such as cytotoxicity. In this
article, the authors have focused on cryptolactone A1, A2,
B1, and B2, colorless polyketide
lactones, isolated from a colorless aphid, Cryptomyzus sp.,
and accomplished the asymmetric total syntheses of these compounds, their
analogs bearing shorter carbon chains, and their antipodes. The investigation
of structure-activity relationships among these compounds was carried out and
revealed that both enantiomers exhibited similar cytotoxic properties towards
HL-60 cell lines. However, compounds with shorter carbon chains were less
cytotoxic than the others.
Organic reactions using
dearomatization have attracted much attention as a new approach to constructing
complicated cyclic molecules. This paper describes the regioselectivity of
nucleophilic addition of organolithium species (in particular, n-BuLi and sec-BuLi) to various aromatic lactones. The results of many
experiments indicated that the regioselectivity varied greatly depending on
various factors, such as the bulkiness of both substrates and organolithium
species, and types of solvent and cosolvent. It is particularly interesting that the
reactions mechanism of the addition of organolithium species differed between n-BuLi (via ionic process) and sec-BuLi (via one
electron transfer process).
Cutting-edge contributions from invited poster
presentations providing significant research works in the fifth International
Symposium for Medicinal Sciences (ISMS) in the 139th Chiba annual meeting in
2019 are assembled for the Current Topics section in this issue of the Chemical
and Pharmaceutical Bulletin.
The principal catalytic reaction of ferric
lipoxygenases is dioxygenation of polyunsaturated fatty acids under normoxia.
On the contrary, at a lower oxygen content, lipoxygenases concomitantly convert
polyunsaturated fatty acids and their hydroperoxides into fatty acid
allyl-radicals and fatty acid alkoxyl radicals, respectively, through
one-electron redox reaction. The former radicals simultaneously react with
oxygen molecule, producing fatty acid peroxyl radicals. In general, free
radicals tend to abstract one electron from molecules. However, fatty acid
alkoxyl radicals donate one electron to the aggressive free radicals including
fatty acid peroxyl radicals, resulting in the oxo-fatty acids generation, which
act as PPAR agonists.
Optogenetics
is a new technology to control neural activity by light using ChRs. ChRs now
used in optpgenitics are mostly sensitive to blue-green light (430-550 nm), and
have several limitations. To overcome these problem, the development of
red-shifted ChRs are eagerly
required. In this paper, six kinds of new chromophores with one
double bond inserted into the polyene side chain of retinal (A1) or
3,4-didehydroretinal (A2) were prepared. Among them, A2-10ex (an extra double
bond was inserted at C10-C11 position of A2) bound with ChrimsonR to afford new
ChR with the greatest red-shifted absorption peak at 654 nm.
Phytochemical analysis of the whole Helleborus foetidus plants
identified 28 steroidal glycosides, including 20 novel spirostanol glycosides
and a novel furostanol glycoside. The structures of the newly identified
compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic
cleavage. Three isolated compounds
were determined to be spirostanol trisdesmosides, which are unique in structure
bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone
unit. The isolated compounds were evaluated for cytotoxic activity against
HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells,
and several compounds exhibited moderate cytotoxic activity.
The
lessons from nature on biosynthesis of natural products might be beneficial for
synthetic organic chemists to design unique synthetic approaches as well as to
facilitate development of new synthetic methodologies. This review emphasized
the merits of biosynthetic consideration in the chemical synthesis of complex natural
products by describing the total syntheses of Lycopodium alkaloids and monoterpenoid indole alkaloids conducted
in author’s laboratory.
Various dimeric compounds comprising two
structurally different indole units are ubiquitous in nature. These compounds are
a pharmaceutically important class of natural products because several
compounds in this class exhibit display greater potency and unique biological
activities compared with the corresponding monomeric compounds. In particular, these dimeric
compounds, which possess molecular weights that deviate from Lipinski’s rule,
are anticipated to be useful as new drug candidates in the middle molecule drug
discovery. This review presents an overview of efficient convergent
syntheses of dimeric indole alkaloids, haplophytine, and T988s with the development of synthetic
methodologies for linking the two indole units.
A new efficient delivery method of oligonucleotide
(ON) therapeutics is developed. Here, antisense ON and small interfering RNA
(siRNA) with disulfide-masked amino units were designed and synthesized for efficient
intracellular delivery. The developed method actually enabled direct delivery
of these ON into the cytosol, where these ON showed the targeted silencing
effects, with minimal cytotoxicity. The molecular design and evaluation reported
in this article would be very informative for further developing efficient
cytosol-delivery methods of therapeutic ONs for medicinal application.
The
structural characteristics of the fractions from Ephedra Herb extract (EHE)
having c-Met kinase inhibitory effects and the fractions from ephedrine
alkaloids-free Ephedra Herb extract (EFE) having analgesic and anti-influenza
activities were characterized. The fractions comprised high-molecular-mass
condensed tannins, which were mainly of the procyanidin B and partly
procyanidin A types, including pyrogallol- and catechol-type flavan 3-ols as the
extension and terminal units. HPLC and gel permeation chromatography (GPC)
analyses estimated that the ratio of pyrogallol- and catechol-type was
approximately 9:2 and the weight-average molecular weight based on polystyrene
standard was >45,000. The authors propose
GPC-based analysis as the quality method for evaluating of high-molecular-mass
condensed tannin in EHE and EFE.
Novel
reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and
applied to the synthesis of biofunctional molecules and some
medicine-candidates. 1) Development of introduction of C1-unit using
cyanophosphates (CPs). 2) Carbene-generation from CPs and its application to
organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions
of medium-sized cyclic thionocarbonates containing a sulfur atom and their
application to natural product synthesis. 4) Stereoselective synthesis of novel
b-imidazole C-nucleosides via diazafulvene
intermediates and their application to investigating ribozyme reaction
mechanism. 5) Developments of novel histamine H3- and H4-receptor
ligands using new synthetic methods involving Se or Sn atoms.
Because lysine modifications on proteins
control various cellular processes and aberrations of the modifications are
associated with various diseases, chemical modulation of lysine-modifying
enzymes is interesting as a method to regulate the cellular functions or as a
therapeutic strategy. Therefore, the author has identified some modulators of
lysine-modifying enzymes. To find the modulators, the author has combined
conventional drug design with “strategic chemistry approaches,” such as drug
design based on enzyme catalytic mechanism. In this review, the author’s drug
discovery studies are presented.
This paper
describes that synthesis and evaluation of novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds as indirect AMP-activated
protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of
compounds inhibited cell growth of MDA-MB-453 but not that of SK-BR-3. The initial
structure optimization of the lead compound 4a led to the discovery of compound 4f with potent AMPK activation activity and poor aqueous solubility.
By further optimizing 4f, promising compound
25 was found out as a potent AMPK activator
with good
aqueous solubility.
Euglena gracilis
EOD-1, produces large quantities of paramylon, has been reported to function as
a dietary fiber. However, the morphometric analysis of paramylon has not been
conducted so far. The authors attempted to
observe the detailed three-dimensional structure of paramylon by FIB/SEM. The
inside of paramylon particles was comprised of a dense structure with no
evidence of the presence of large pores and gaps. The specific surface area of paramylon particles was not as large as activated charcoal,
but similar to those of plant starches, indicating that the
cholesterol-lowering effect of paramylon cannot be simply attributed to its
adsorption ability.
The ubiquity of the biaryls with heteroatoms in and on the rings, are
of importance in organic chemistry as building blocks of functional compounds,
such as bioactive natural products, pharmaceuticals, and chemicals. Therefore, the cross-couplings can provide powerful tools for the
construction of biaryls and the development of a novel coupling method has been
intensively studied by synthetic chemists. In the present study, the author
demonstrated the metal-free oxidative couplings of two different aromatic C-H
bonds in electron-rich arenes for producing biaryls based on new strategies and
concepts using hypervalent iodine reagents.
Pharmacopoeias have provided public
standards to help ensure the quality of drugs. As of 2018, pharmacopoeias exist
in 56 countries and 3 regions. These pharmacopoeias have contributed to the
quality assurance of drug substances and products by providing common standards
for users in each region/country. As drug markets and supply chain is
globalizing, the
independent standards in each pharmacopoeia increase users’ burden of having to
perform analytical procedures in different ways and using different acceptance
criteria to satisfy pharmacopoeia requirements that vary across regions. To contribute to the further convergence of pharmacopoeial
standards, the authors conducted a comparative
study of the pharmacopoeias in Japan, Europe, and the United States.
Four
new triterpene glucosides and two megastigmanes were isolated from the leaves
of Diospyros maritima. The structures
of triterpene glucosides were elucidated by a sequential hydrolysis of
glycosidic and ester bonds using different enzymes to give partial hydrolyzed
intermediates and finally aglycones. Hydrolysis of 28-O-ester bonded glucose by a crude glucosidase may give a new tool
in triterpene chemistry. Two new
megastigmanes were also isolated and their structures were unambiguously
elucidated using the modified Mosher's method and two megastigmanes were
chemically correlated by NaBH4 reduction of the ketonic one.