There is a great need for reagents
that are environmentally benign, easy to
handle, inexpensive, and safe in organic synthesis. In this context, the authors have developed hydrophilic
polyacrylamide-gel based triazine-type condensing reagents, PAG-Trz-Cls, which
were synthesized from inexpensive materials via radical polymerization. PAG-Trz-Cls
are non-hygroscopic solid, high-loading, well-swollen in water and alcohol.
Owing to these features, condensation between highly polar carboxylic acids and
amines in an aqueous solvent successfully proceeded, and purification of the
resulting amides can be readily carried out by filtration.
“Soft” nature of copper catalysis enabled two types
of chemoselective reactions. First, C-C bond forming reactions at an anomeric
carbon of unprotected aldoses were developed by taking advantage of orthogonal
reactivity between “soft” organocopper species and “hard” polar functional
groups, free hydroxy groups. Second, preferential reaction between “soft”
copper species and “soft” C-C multiple bonds enabled difunctionalization of the
multiple bonds by controlling the reaction order of three reactive species. Well-controlled
stereo- and/or regioselectivity of the reactions is another important feature
of the copper catalysts.
Omphalotus japonicus (Tsukiyotake in japanese) is
well-known as a poisonous mushroom in Japan. In this study, the authors isolated
six new sesquiterpenes, four known sesquiterpenes and two known steroids from
the fruiting body of O. japonicus with column chromatography,
solid-phase extraction (SPE), and HPLC. The chemical structures were determined
with NMR, MS and IR spectra. Relative configuration was determined with NOE
correlations and absolute configuration was determined with ECD calculation. Three
new compounds showed
growth-restoring activity against mutant yeast via calcium-signal transduction.
This paper describes that the synthesis and evaluation of novel indirect adenosine
monophosphate-activated protein kinase (AMPK) activators. The series of
compounds selectively inhibited cell growth in several human breast cancer cell
lines by activating AMPK. The back-up medicinal chemistry synthetic research on
ASP4132, a previously reported clinical compound that acts as an indirect AMPK
activator, led to the successful identification of 27b as a second-generation clinical
candidate with promising profiles such as high aqueous solubility and less human
Ether-a-go-go Related Gene (hERG) channel inhibitory activity.
The 2, 5-diketopiperazine (DKP)
scaffold exists in many natural product families, ranging from fungi and
bacteria to the plant kingdom and mammals. Because of the privileged structure and
the ability to bind vast receptors, it has become extremely attractive
synthetic target for the assembly of natural product-like libraries for drug
discovery. In this article, a series of novel derivatives containing DKP
skeleton were developed as targeted inhibitors. Several compounds exhibited
distinct HDAC1 inhibitory activities and showed antiproliferative activities
against K562 and HL-60 tumor cell line.
Instrument-dependent factors affecting the
precision in the atomic force microscopy stiffness measurement of nanoscale
liposomes was examined. The tip shape evaluation method previously developed can be widely used via IC-mode force curve
measurements as well as via QI mode. It was also revealed that spatial
drift of the cantilever position was instrument-dependent factors which could
affect the precision of liposome stiffness measurements in the case of IC-mode
force curve measurement. These findings will promote the usage of the AFM
stiffness measurement method for the characterization of lipid
nanoparticle-based drug delivery systems.
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.
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
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
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.
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.
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.
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.
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.