This article describes the discovery of
potent pyrimidoindazoles as PDE10A inhibitors by using the method of
fragment-based drug discovery (FBDD). The authors made use of X-ray analysis
well to obtain PDE10A inhibitors. In addition, they designed well-balanced
compounds in light of physicochemical property and inhibitory activity. This
study showed that FBDD approach is effective for the discovery of PDE10A
Methyl-b-cyclodextrin (M-b-CyD) exhibits an antitumor activity,
although its tumor-selectivity is low.
Meanwhile, hyaluronic acid (HA) is known as a promising tumor
targeting ligand, because various cancer cells overexpress CD44, a HA-binding glycoprotein. In this study, to develop a tumor-selective
delivery system for M-b-CyD, the authors designed
a supramolecular complex of M-b-CyD with adamantane-grafted HA (Ad-HA/M-b-CyD) and evaluated it as a tumor-selective antitumor
agent. Eventually, Ad-HA/M-b-CyD showed the superior cytotoxic activity via CD44-mediated endosomal
pathways, suggesting that Ad-HA/M-b-CyD has the potentials as a
tumor-selective antitumor agent.
Cutting-edge contributions from invited
poster presenters providing
significant research works in the third
International Symposium for
Medicinal Sciences (ISMS) in the 137th
Sendai annual meeting in 2017 are
assembled for the Current Topics section in
this issue of the Chemical and
Aggregation of amyloid β-peptide (Aβ) is closely linked to several neurodegeneration diseases including Alzheimer’s disease. Molecular dynamics simulations were performed to clarify the initial stage of Aβs interaction on the lipid membrane that mimicked a micro-domain on the neuronal cell surface. Stable complexes of Aβ peptides were not rapidly generated in simulation, instead a binding of two Aβs was gradually developed. In a stable two Aβs complex, one is bound to the membrane surface, while the other is attached to the first one without strong contact with membrane. A parallel β-sheet structure is formed between the C-terminal sides of them.
Nucleosides and nucleotides have fascinated chemists and biologists, because nucleosides and nucleotides are of vital importance not only as components of ribo- and deoxyribonucleic acids in central dogma, but also as a wide variety of biofunctional molecules. This current topic summarized the recent progress on chemical ligation of oligonucleotides, nucleoside antibiotics, unnatural base pairs, antiviral/antitumor nucleoside analogues, protecting groups for oligonucleotide prodrugs, and nucleotide second messengers.
Three divergent total syntheses of heteropolycyclic natural product groups, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. These syntheses employed the strategy for designing a late-stage pluripotent common synthetic intermediate that is prepared via the formulation of original and innovative transformations. Brief description of the philosophy and criteria for choosing synthetic targets and common synthetic precursors, as well as the details of development of the overall synthetic schemes mapped around the designed common intermediate are discussed.
The paper describes solid-phase synthesis
of peptidoglycan biosynthesis
precursor and its analogues: Park
nucleotide (1), neryl-lipid I (2) and
neryl-lipid II (3). The higher acidity of
activators accelerated the
reaction rate of diphosphate formation, and
formation was accomplished by using
triazolium triflate (29) as an
activator. The synthetic strategy enables
to prepare 1-3 in a short time
with a single purification. These analogues
could be useful as chemical
probes for discovering novel antibacterial
agent and elucidating mechanistic
This study showed that secoiridoid glycosides are the
main constituents of the twigs of L.
obtusifolium, and two new secoiridoid derivatives, obtusifoliside A and B (1, 2),
were isolated from this plant. Moreover, anti-inflammatory, and neuroprotective
activities of the isolated compounds were investigated. Among the
isolates, the new compound 2 showed remarkably better anti-inflammatory effects without cell
toxicity. This study could be useful for the development of novel
anti-inflammatory and neuroprotective agents.
progress in medicinal chemistry has contributed to develop a variety of drug
candidates in pharmaceuticals. Focusing on the significant progress in the
fields shown in the cover, the present current topics include three reviews, “New
Gateways to Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method Utilizing
Hydrogen as a Catalyst Activator,” “7-Azaindole: A Versatile Scaffold for
Developing Kinase Inhibitors” and “Discovery and Development of Muscarinic
Acetylcholine M4 Activators as Promising Therapeutic Agents for CNS Diseases”
and one communication, “A Peptide–Glycolipid Interaction Probed by Retroinverso
of toxic gas surrogates can contribute to improving the safety and practicality
for implementation of synthetic organic reactions. This review describes the
author’s discovery, development, and applications of toxic gas surrogates. Various
carbonyl compounds were obtained by Pd-catalyzed carbonylative transformations
under mild conditions using novel carbon monoxide (CO) surrogates. Mechanistic
studies of the CO generation and gram-scale syntheses using CO surrogates were successfully
performed. Furthermore, the use of an inexpensive sulfur dioxide surrogate led
to the development of unprecedented selective syntheses of sulfonamides and
Analytical methods for disease diagnosis require high sensitivity and specific methods. For neonatal mass screening of congenital metabolic disorders, a 3 mm diameter disc of dried filter paper blood obtained from one drop of newborn blood is used, and one disc contains about 4 μL of blood. Diagnosis is performed by measuring hormones and genes in this disc. In hormone analysis, chemiluminescent enzyme immunoassay was developed. In genetic analysis, pyrophosphate generated by PCR amplification reaction or DNA fragment as amplification product was analyzed by luciferase bioluminescence method and capillary electrophoresis, respectively. In addition, identification of reactive oxygen species generated from natural medicines and antianginal drugs and their physiological action mechanism are described.
This paper describes the development of a synthetic method for tetrahydrobiphenylenes and derivatives based on a palladium(0)-catalyzed C(sp2)−H functionalization. This is a new direct method for accessing partially hydrogenated biphenylenes. The derivatization of a tetrahydrobiphenylene is also reported.
A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, compound 18K was shown to inhibit protein tyrosine phosphatase 1B (PTP1B) activity potently and non-competitively (IC50=0.25 μM). Molecular dynamics simulation demonstrated that 18K binds to the allosteric site of PTP1B. Compound 18K showed high oral absorption in mice, rats, and beagles, and markedly reduced plasma glucose levels, TG levels, and HOMA values with no side effects at 30 mg/kg (p.o.) for one week in db/db mice. In conclusion, the substituted benzoylsulfonamide is a novel scaffold of non-competitive allosteric PTP1B inhibitors, and compound 18K is a promising candidate for an efficacious and safe anti-diabetic drug with anti-obesity effects.
This article describes the discovery of a new class of lead compound 5 by combining structural features from previously disclosed two chemotypes, represented by 3 and 4, and subsequent medicinal chemistry efforts to optimize potency, PDE selectivity, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts culminated in the identification of 20, which demonstrated significant elevation of cGMP levels in rat brains, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.
The authors designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group, such as 7a, also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.
Jellies for oral administration are dosage forms that contain water and heat is generally applied to the jellies during the manufacturing process. Therefore, it is difficult to formulate drugs that may be affected adversely by water and/or heat. To solve this problem, the authors develop a powder form of gel as a novel dosage form (dry jelly) that is converted to gel after addition of water at the time of administration. The concept of dry jelly gelation by water addition is shown in graphical abstract. In the article, the critical factors affecting gelation phenomena as well as physical and drug dissolution properties of the gel prepared from drug-containing dry jelly are evaluated.
Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This article examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness were examined in terms of surface free energy and dispersibility. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR-CI is a useful methodology for improving the understanding of tablet manufacturing blending processes.
artificial neural network (4LNN) was employed to predict dissolution data
from physicochemical and powder properties of active pharmaceutical
ingredients (APIs) formulated in various kinds of tablets. Causal factors of
APIs in the input layer were simplified into the nodes in the 1st hidden
layer, properly integrated information would then be transferred to the nodes
in the 2nd hidden layer, and finally the secured outcome was delivered in the
output layer. An excellent model for the prediction of dissolution data was
achieved with 4LNN method. The function of 4LNN was appreciably better than
that of conventional three-layered model.
In the article, a
series of novel disulfides containing 1,3,4-thiadiazole moiety were
synthesized and evaluated for their in vitro antiproliferative activities using CCK-8 assay against human
cancer cell lines A549, HeLa, SMMC-7721 and normal cell lines L929. The
bioassay results indicated that most of the tested compounds exhibited
antiproliferation with different degrees, and some compounds inhibited the
proliferation better than positive control 5-fluorouracil against various
cancer cell lines. Furthermore, all compounds showed weak cytotoxic effect
against L929 cells. Therefore, the results suggest that the substituent
groups are vital for improving the potency and selectivity of this class of
described that membrane-permeable bases accelerated the release of
encapsulated drug, doxorubicin, from DOXIL by using a HPLC column for