In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure–activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

Methyl-β-cyclodextrin (M-β-CyD) exhibits cytotoxic activity, and has the potentials as an antitumor agent. However, a tumor-selectivity of M-β-CyD is low, leading to low antitumor activity and the adverse effects. Meanwhile, hyaluronic acid (HA) is known as a promising tumor targeting ligand, because various cancer cells overexpress CD44, a HA-binding glycoprotein. In the present study, to develop a tumor-selective delivery system for M-β-CyD, we designed a supramolecular complex of M-β-CyD with adamantane-grafted HA (Ad-HA/M-β-CyD) and evaluated it as a tumor-selective antitumor agent. M-β-CyD formed a stable complex with Ad-HA (K_c>10⁴ M⁻¹). In addition, Ad-HA/M-β-CyD formed slightly a negative-charged nanoparticle with ca. 140 nm of a particle size, indicating the favorable physicochemical properties for antitumor agents. Ad-HA/M-β-CyD showed the superior cytotoxic activity via CD44-mediated endosomal pathways in HCT116 cells (CD44(+)), a human colon cancer cell line. In addition, cytotoxic activity of Ad-HA/M-β-CyD was induced by apoptosis. These results suggest that Ad-HA/M-β-CyD has the potentials as a tumor-selective supramolecular antitumor agent.

Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ₄₂ peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.

The divergent total syntheses of three types of heteropolycyclic natural products, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. A strategy involving a late-stage pluripotent common synthetic intermediate prepared via original and innovative transformations was employed. A brief description of the philosophy and criteria for choosing the synthetic targets and common synthetic precursors, as well as details regarding the development of the overall synthetic schemes from a common intermediate are discussed.

A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4 d) with a single purification step to synthesize the molecules by solid-phase synthesis.

Two new secoiridoid glycosides, obtusifolisides A and B (1, 2), together with 7 known secoiridoid glycosides (3–9) were isolated from the twigs of Ligustrum obtusifolium. The chemical structures of new compounds were determined by a spectroscopic data analysis, including one and two dimensional (1D-, 2D)-NMR, High resolution-MS, and experiments involving chemical reactions. The isolated secoiridoid glycosides were evaluated for their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV-2 murine microglia cells. Compounds 2, 5, 6, 8, and 9 significantly reduced the production of nitric oxide (NO), with IC₅₀ values of 5.45, 11.17, 14.62, 15.45, and 14.96 µM, respectively. None of the compounds were toxic to the cells. Additionally, we evaluated the neuroprotective effects of compounds 1–9 on nerve growth factor (NGF) induction in a C6 rat glioma cell line. Compounds 2 and 6 upregulated NGF secretion to 155.56±7.16%, and 139.35±11.65%, respectively, without significant cell toxicity.

The use of toxic gas surrogates in organic reactions instead of the gas itself contributes to enhancing the safety, practicality, and efficiency of the reactions involved. Our efforts toward the creation of toxic gas surrogates and the development of a series of catalytic reactions using these surrogates are described. Improvements in substrate scope during the hydroesterification of alkenes using formates facilitated by the Ru–imidazole catalyst system provided the opportunity to discover that phenyl formate is a useful carbon monoxide (CO) surrogate for the generation of CO and phenol under weakly basic conditions. This discovery triggered the development of highly reactive but stable CO surrogates and a variety of Pd-catalyzed carbonylative transformations. N-Formylsaccharin facilitated the use of additional nucleophiles in carbonylation reactions that provided access to a variety of carbonyl compounds. Detailed experimental and theoretical mechanistic studies into the generation of CO from phenyl formate suggest that CO generation proceeds via a concerted E2 α-elimination. Furthermore, a known surrogate of sulfur dioxide was applied for the first time to the selective syntheses of cyclic sulfonamides and sulfinamides, confirming that the surrogate operates as an “S=O” source. Notably, the reactions described herein are scalable and can be performed without the use of external toxic gases and specialized reaction vessels; they are easy and simple to perform and demonstrate enormous potential for industrial application.

One important aspect of analytical chemistry research in the pharmaceutical sciences is the development of diagnostic and therapeutic analyses for disease, and the development of analytical methods for elucidating the causes of disease. I have been focusing on developing a highly sensitive method for measuring trace amounts of specific components in biological samples. This research can be roughly divided into three approaches: the use of immunoassays and DNA hybridization as methods utilizing specific affinities, the use of capillary electrophoresis as a highly sensitive and rapid separation method, and the use of chemiluminescence and bioluminescence reactions. The components being measured are compounds such as hormones, tumor markers, drugs, reactive oxygen species and genes in biological samples for the purpose of developing therapies for the prevention and treatment of diseases.

Tetrahydrobiphenylene consists of cyclobutene fused with benzene and cyclohexene rings. In this paper, a direct method for synthesizing tetrahydrobiphenylenes based on a palladium (Pd)(0)-catalyzed C(sp²)–H functionalization was investigated. The developed method was applied to the synthesis of several tetrahydrobiphenylenes having an oxygen functionality at the ring juncture. The derivatization of a tetrahydrobiphenylene is also reported.

A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzamide (compound 18K) was identified as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with potent and selective inhibitory activity against PTP1B (IC₅₀=0.25 µM). Compound 18K functioned as a non-competitive inhibitor and bound to the allosteric site of PTP1B. It also showed high oral absorption in mice (the maximum drug concentration (C_max)=45.5 µM at 30 mg/kg), rats (C_max=53.6 µM at 30 mg/kg), and beagles (C_max=37.8 µM at 10 mg/kg), and significantly reduced plasma glucose levels at 30 mg/kg/d (per os (p.o.)) for one week with no side effects in db/db mice. In conclusion, the substituted benzoylsulfonamide was shown to be a novel scaffold of a non-competitive and allosteric PTP1B inhibitor, and compound 18K has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations of the physiological and pathophysiological effects of allosteric PTP1B inhibition.

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, 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 progesterone receptor (PR) controls various physiological processes, including the female reproductive system, and nonsteroidal PR ligands are considered to be drug candidates for treatment of various diseases without significant adverse effects. Here, we 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 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, as stipulated in the Japanese Pharmacopeia, 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, we tried to develop a powder form of gel as a novel dosage form (dry jelly: jelly medicine extemporaneously prepared) that is converted to jelly after addition of water at the time of administration. For this purpose, a basic gel formulation consisting of pectin, glucono-δ-lactone, dibasic calcium phosphate hydrate, and sucrose was investigated to evaluate the critical factors affecting gelation phenomena. The gel form was developed by adjusting the amount of each component of the formulation and of water added. Gelation occurred even with hard water containing metal ions (hardness of approximately 304 mg/L), and no changes in gel hardness occurred. The desired gel hardness could be controlled by adjusting the amount of water. The gel hardness changed over time after the addition of water, but this change did not affect the dissolution behavior of drugs formulated in the dry jelly.

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 study examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness. These effects were examined in terms of surface free energy and dispersibility. Dissolution, disintegration, and hardness were evaluated for tablets manufactured from powder mixtures of each MgSt hydrate form and other components, including ethenzamide as an active ingredient, using different mixing times. The surface energy was evaluated for MgSt mono- or dihydrate powder mixtures with a surface tensiometer. For dispersibility, the adhesion states of MgSt hydrates to other components were visually observed via near-infrared (NIR) chemical imaging. The dispersion behavior of MgSt hydrates was examined by quantitative evaluation of skewness and kurtosis of histograms, based on NIR images, and domain size estimated from their binary images. 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 chemical imaging is a useful methodology for improving the understanding of tablet manufacturing blending processes.

A large number of dissolution data were measured and integrated into a previously constructed tablet database composed of 14 kinds of compounds as model active pharmaceutical ingredients (APIs) with contents ranging from 10 to 80%. The database has contained physicochemical and powder properties of APIs, together with basic physical attributes of tablets such as the tensile strength and the disintegration time. In order to enhance the value of this database, drug dissolution data are essential to improving key information for designing tablet formulations. A four-layered artificial neural network (4LNN), newly implemented in commercially available software, was employed to predict dissolution data from physicochemical and powder properties of APIs. Our results showed that 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, despite both models adopting the same number of nodes and algorithms for activation functions. Furthermore, linear regression models resulted in poor prediction of dissolution data.

A series of novel disulfides containing 1,3,4-thiadiazole moiety were designed, synthesized, and the structures of all products were identified by spectral data (IR, NMR, and high resolution (HR)-MS). Their in vitro antiproliferative activities were evaluated using 2-(2-methoxy-4-nitro-phenyl)-3-(4-nitro-phenyl)-5-(2,4-disulfopheyl)-2H-tetrazolium monosodium salt (CCK-8) assay against human cancer cell lines, A549 (human lung cancer cell), HeLa (human cervical cancer cell), SMMC-7721 (human liver cancer cell) and normal cell lines L929. The bioassay results indicated that most of the tested compounds 6a–k, 7a–k and 8a–k exhibited antiproliferation with different degrees, and some compounds showed better effects than positive control 5-fluorouracil (5-FU) against various cancer cell lines. Among these compounds, compound 6e exhibited the most potent inhibitory activity against A549 cells with IC₅₀ value of 3.62 µM. Compounds 6i, 7a, 7g, 8a and 8b showed significantly antiproliferative activities against HeLa cells with IC₅₀ values of 3.88, 3.76, 3.59, 3.38 and 3.12 µM, respectively. Compounds 6a, 7a and 8a owned high antiproliferative activities against SMMC-7721 cells with IC₅₀ values of 2.54, 2.69 and 2.31 µM, respectively. Furthermore, all of the tested compounds showed weak cytotoxic effect against the normal cell lines L929. Based on the preliminary results, the substituent groups are vital for improving the potency and selectivity of this class of compounds.

In recent years, nanomedicines have received growing attention in a range of medical applications, including selective drug delivery technology. In this context, the analysis of liposome stability and drug release from liposomes is of particular importance, as the efficacy of a nanomedicine is determined by the release of the encapsulated drug. We investigated the influence of the surrounding environment on the stability and release of the encapsulated drug (i.e., doxorubicin) from DOXIL. Thus, for the purpose of this study, we selected the liposomal anticancer drug, DOXIL, as a typical nanomedicine, and investigated the influence of the surrounding environment on release of doxorubicin from DOXIL. We found that two pathways existed for doxorubicin release, namely the collapse of DOXIL, and an increase in the permeability of the lipid bilayer. DOXIL collapse occurred upon the addition of high concentrations (>60%) of a methanol solution, while an increase in permeability occurred at temperatures above the phase transition temperature of the DOXIL lipid bilayer, under basic conditions, and in the presence of membrane-permeable bases (e.g., Tris). As DOXIL is particularly stable and limited collapse of DOXIL occurred under physiological conditions, it is expected that doxorubicin release within the body took place through permeability changes in the lipid bilayer of the DOXIL structure.