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.
The authors investigate the effect of TQHXD on the expressions of related proteins of the blood-brain barrier (BBB) and analysis of constituents in the cerebrospinal fluid (CSF) on cerebral ischemic rats. They found that TQHXD could up-regulate ZO-1, occludin, claudin-5 expressions and down-regulate AQP-4, MMP-9 expressions. Moreover, muscone, ligustilide and hydroxysafflor yellow A in CSF were also detected. These compounds could be identified as the main active ingredients of TQHXD on protecting the damaged BBB.
A four-layered 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 compounds.
The authors described that membrane-permeable
bases accelerated the release of encapsulated drug, doxorubicin, from DOXIL by
using a HPLC column for nanomedicine analysis.
article, a mild deacylation method for 3,5-dinitrobenzoates, which are often
used to improve their diastereomeric or enantiomeric purities by
recrystallization and also widely used as a pro-nucleophile in the Mitsunobu reaction,
has been developed by using methanolic solutions of amines, such as
dialkylamines. Removal of dinitrobenzoyl groups undergoes without affecting existing
acetyl groups and also without affecting stereochemistry in α-hydroxy
ketone. Encouraged by the promising versatility, the authors successfully
applied this method to the efficient asymmetric synthesis of Colorado potato
Since an antileukemic ansa macrolide, maytansine was
first isolated from Maytenus ovata,
plants belong to Celastraceae draw the attention of natural product chemists.
The authors focused on the plants collected in Okinawa Islands, and
Celastraceae plant, Microtropis japonica
was chosen for the target material. ent-Labdane
glycoside and 6'-O-(2"S,3R")-2"-ethyl-2",3"-dihydroxybutyrates of aliphatic
alcohol β-D-glucosides branches have been isolated from leaves and
branches respectively. Current investigation of leaves afforded further ent-labdane
of aliphatic alcohol β-D-glucosides, ursane-type triterpene diglucoside,
and flavonol glycoside.
Density functional theory calculations were
performed to explore the mechanism of Ni-catalyzed cross-coupling reactions
involving organo-lithium and -zinc reagents though ethereal C–O bond cleavage.
In comparison with our previous mechanistic study on etheric Kumada–Tamao
reaction, it shows that the the Ni(0)-ate complex-mediated reaction pathway is
a new and general mechanism for ethereal cross-coupling reactions, which can
well explain the experimental findings for several ethereal C–O bond cleavage
couplings. The present work also
suggests that the anionic character of organometallic nucleophiles can change
oxidative addition mechanisms/pathways, which may provide new reactivity and
We evaluated the adhesion force of the film
coating layer to the surface of tablets prepared using an external lubrication
method. Increasing lubrication decreased wettability of the tablet surface.
However, no change was observed in the adhesion force of the film coating
layer. The magnesium stearate distribution state on the tablet surface was
assessed and the lubricant was uniformly dispersed in the external lubrication
samples. The distribution state of the lubricant affects the adhesion force of
the film coating layer, and external lubrication maintained sufficient
lubricity and adhesion force of the film coating layer with a small amount of lubricant.
Four new lignans, a furofuran lignan medioresinol B (10) and three tetrahydrofuran lignans
kobusinol C (16), 7'-methoxy magnostellin
A (21), and mangnostellin D (23), along with 19 known lignans, were
isolated from the flower buds of Magnolia
biondii Pamp. The structures of the isolates were elucidated using
spectroscopic analysis, mainly one- and two-dimensional NMR, high resolution
mass spectrometry, and circular dichroism techniques as well as Mosher’s
esterification method. The anti-allergic effects of the isolated compounds were
evaluated by analyzing the inhibition of interleukin-2 (IL-2) expression in
Jurkat T-cells. Compounds 11−14 reduced IL-2 expression in a
Fluorophores undergoing excited-state intramolecular proton transfer (ESIPT) exhibit several unique characteristics. In the paper, a range of 7-hydroxy-3-methyleneisoindolin-1-ones is investigated as new ESIPT fluorophores. In fact, dual emission is observed in alcohols and DMSO; ~380 and ~530 nm (exc. = ~336 nm), and a single emission is observed (~500 nm) in EtOH-H2O binary mixtures. Furthermore, the wavelength of fluorescence maxima is dependent on the dielectric constant of the solvent, suggesting their potential utility for monitoring aqueous environments.
The hedgehog (Hh) signaling pathway performs important roles in cellular process, however, in many cancer cells Hh signaling is aberrantly activated, which has provided a strong impetus for the development of Hh pathway inhibitors. In the paper, a series of heterocyclic flavonoids are prepared and evaluate their Hh signaling inhibitory activity. As a result, some of the synthetic flavonoids show good Hh inhibitory activity as well as cytotoxicity toward human cancer cells. Western blotting analyses also reveal that PTCH and GLI1 expression is reduced.
This paper focuses on melt adsorption as manufacture method of wax matrices to control particles size of granules more easily than melt granulation, and demonstrated for the first time that melt adsorption using a hydrophobic material has the potential capability to control the particle size of granules and offers the possibility of application as a novel controlled release technique.
Cellular functions are mediated by a great variety of enzymes, and altered enzymatic functions are often observed during disease onset and progression. Therefore, discovering the novel connection between the functions of enzymes and specified diseases is the key to developing novel diagnostic methods, as well as therapeutic drugs. In this review, we describe the recently advancing field of chemical biology that aims to discover and characterize disease-related alternation of enzymatic functions, which can be termed as “enzym-omics (omics of enzymes)”. The review covers several key technologies that can be considered as the representative experimental systems used for this purpose.
In this review, new and reliable procedures for the construction of diverse ring systems based on the chemistry of sp-hybridized species are described. The synthetic application includes (i) multi-cyclic skeletons by the Rh-catalyzed reaction of allenes with other π-components such as alkyne, alkene, and allene, (ii) hetero- and carbocycles from appropriate allenes and nucleophiles, and (iii) natural products and related compounds.
This review summarizes author’s recent reports on Pd(0)-catalyzed benzylic C(sp3)-H functionalization for the synthesis of various heterocycles including oxindoles, spirooxindoles, 2-arylindoles, benzocarbazoles, indolocarbazoles, and indoloquinazolinones. The key feature would be a chemoselective C(sp3)-H activation in the oxindole synthesis. The developed method was successfully applied to the total synthesis of several pyrrolophenanthridine alkaloids as well as a synthesis of the right-hand fragment of benzohopane.
In this communication, development of a new
type of red-shifted channelrhodopsins (ChRs) is described. Optogenetics is a powerful new
technique which allows control of neuronal activity by light, and ChRs are now
widely used in optogenetics due to their function of a light-gated cation
channel. In neuroscience, ChRs responding to a long-wavelength light are eagerly
required, because ChRs now used are maximally sensitive to green and blue light, and does not penetrate tissues. Here developed new type of ChRs model consisted of
red-shifted chromophores (retinal-based enamine-type Schiff bases) and mutated
channelopsin (C1C2-K296G), in which chromophores were incorporated noncovalently. Thus prepared new ChRs
exhibited absorption maxima that were 10-30 nm red-shifted compared with the