Showing papers in "Chemical & Pharmaceutical Bulletin in 2019"

The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy.

Abstract: A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody-drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

Potential Anticancer Activity of Auranofin

Abstract: Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives.

Abstract: New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.

A Review of Biologically Active Natural Products from a Desert Plant Cistanche tubulosa

Abstract: An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.

Different Degradation Mechanisms of Inhibitor of Apoptosis Proteins (IAPs) by the Specific and Nongenetic IAP-Dependent Protein Eraser (SNIPER).

Abstract: Targeted protein degradation by small molecules is an emerging modality with significant potential for drug discovery. We previously developed chimeric molecules, termed specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which induce the ubiquitylation and proteasomal degradation of target proteins. This degradation is mediated by the IAPs; the target proteins include bromodomain-containing protein 4 (BRD4), an epigenetic regulator protein. The SNIPER that degrades this particular protein, SNIPER(BRD)-1, consists of an IAP antagonist LCL-161 derivative and a bromodomain and extra-terminal (BET) inhibitor, (+)-JQ-1. SNIPER(BRD)-1 also degrades a cellular inhibitor of apoptosis protein 1 (cIAP1) and an X-linked inhibitor of apoptosis protein (XIAP), the mechanisms of which are not well understood. Here, we show that the degradation of cIAP1 and XIAP by SNIPER(BRD)-1 is induced via different mechanisms. Using a chemical biology-based approach, we developed two inactive SNIPERs, SNIPER(BRD)-3 and SNIPER(BRD)-4, incapable of degrading BRD4. SNIPER(BRD)-3 contained an N-methylated LCL-161 derivative as the IAP ligand, which prevented it from binding IAPs, and resulted in the abrogated degradation of cIAP1, XIAP, and BRD4. SNIPER(BRD)-4, however, incorporated the enantiomer (-)-JQ-1 which was incapable of binding BRD4; this SNIPER degraded cIAP1 but lost the ability to degrade XIAP and BRD4. Furthermore, a mixture of the ligands, (+)-JQ-1 and LCL-161, induced the degradation of cIAP1, but not XIAP and BRD4. These results indicate that cIAP1 degradation is triggered by the binding of the IAP antagonist module to induce autoubiquitylation of cIAP1, whereas a ternary complex formation is required for the SNIPER-induced degradation of XIAP and BRD4.

Structure and Function of Δ9-Fatty Acid Desaturase

Abstract: Δ9-Fatty acid desaturase (Δ9-desaturase) is a rate-limiting enzyme of unsaturated fatty acid biosynthesis in animal cells and specifically introduces a cis-double bond at the Δ9-position of acyl-CoA. Since the chemical structure of fatty acids determines the physicochemical properties of cellular membrane and modulates a broad range of cellular functions, double bond introduction into a fatty acid by Δ9-desaturase should be specifically carried out. Reported crystal structures of stearoyl-CoA desaturase (SCD)1, one of the most studied Δ9-desaturases, have revealed the mechanism underlying the determination of substrate preference, as well as the position (Δ9) and conformation (cis) of double bond introduction. The crystal structures of SCD1 have also provided insights into the function of other Δ9-desaturases, including Drosophila homologs. Moreover, the amino-terminal sequences of Δ9-desaturases are shown to have unique roles in protein degradation. In this review, we introduce recent advances in the understanding of the function and regulation of Δ9-desaturase from the standpoint of protein structure.

Cyclodextrin-Based Molecular Accessories for Drug Discovery and Drug Delivery.

Abstract: Recently, active pharmaceutical ingredients (APIs) have been dramatically expanding from low-molecular weight drugs to peptides, proteins, antibodies, genes, oligonucleotides, cells, and machines. Therefore to develop pharmaceutical technologies and drug delivery systems (DDS) for these APIs, advanced molecules and novel concepts are needed. In this review, we introduce cyclodextrin-based supramolecular accessories such as molecular necklace, molecular earring, and intelligent molecular necklace, and describe their application for pharmaceutical technology and DDS. In addition, we also introduce utility of supramolecular accessories as antitumor drugs. Finally, we propose a new concept in pharmaceutical sciences termed as "supramolecular pharmaceutical sciences," which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences.

Fabrication of Zero-Order Sustained-Release Floating Tablets via Fused Depositing Modeling 3D Printer

Abstract: A three-dimensional (3D) printer is a powerful tool that can be used to enhance personalized medicine. A fused deposition modeling (FDM) 3D printer can fabricate 3D objects with different internal structures that provides the opportunity to introduce one or more specific functionalities. In this study, zero-order sustained-release floating tablet was fabricated using FDM 3D printer. Filaments comprising poorly water-soluble weak base drug, itraconazole (ITZ) and polymers (hydroxypropyl cellulose and polyvinylpyrrolidone) were prepared, and tablets with a hollow structure and different outside shell thicknesses were fabricated. In the 3D printed tablets, ITZ existed as an amorphous state and its solubility improved markedly. As the outside shell thickness of the tablet increased, drug release was delayed and floating time was prolonged. In the tablets with 0.5 mm of the upper and bottom layer thickness and 1.5 mm of the side layer thickness, holes were not formed in the tablets during the dissolution test, and the tablets floated for a long period (540 min) and showed nearly zero-order drug release for 720 min. These findings may be useful for improving the bioavailability of several drugs by effective absorption from the upper small intestine, with floating gastric retention system.

Relationship between Structural Characteristics and Plant Sources along with Pharmacology Research of Quassinoids.

Abstract: Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.

A Retrospective Analysis of the Effect of Tigecycline on Coagulation Function

Abstract: A number of clinical trials demonstrated that tigecycline was effective and well tolerated in the treatment of patients with various bacterial infections, but few literatures had shown the coagulopathy induced by tigecycline. To address this concern, we performed a retrospective analysis to assess the impact of tigecycline treatment on coagulation parameters in 50 patients with bacterial infections in our hospital (Shandong Provincial Hospital, China). These patients were treated with tigecycline at Shandong Provincial Hospital in 2015-2016 at either a recommended (50 mg q12h) or a higher dose (100 mg q12h). Coagulation parameters, including Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT) and D-dimer, were evaluated in order to assess the impact of tigecycline treatment in these severely infected patients. What we found was that the plasma fibrinogen (FIB) level was 4.63 ± 1.56 g/L before tigecycline treatment, and decreased to 2.92 ± 1.23 g/L during treatment, which was statistically significant (p < 0.001). The mean values of aPTT and PT were significantly increased from 39.58 ± 8.72 to 44.05 ± 10.45 s (p = 0.002), and from 15.37 ± 1.53 to 16.37 ± 2.64 s (p = 0.004), respectively. This study demonstrates that treatment of tigecycline could reduce FIB, prolong aPTT and PT. In conclusion, we advise that it is necessary for practitioners routinely monitor coagulation level in at-rick patient populations treated with tigecycline.

Nickel-Catalyzed Hydrocyanation of Allenes and Its Application.

Abstract: Cyano (CN) groups are equivalent to carbonyl as well as amino- and hydroxymethyl groups. Therefore, their catalytic introduction under metal catalysis is an important issue in synthetic organic chemistry. Ni-catalyzed hydrocyanation is one of the most well-investigated, powerful tools for installing a CN group. However, it is still difficult to control chemo- and regioselectivity. In this review, the author uses allenes to enable regio-, stereo-, and face-selective transformations to natural product synthesis and axial chirality transfer.

Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations.

Abstract: As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial. In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results. Alpha linked immunosorbent assay (LISA) methylation assay was performed to test their inhibitory activity against PRMT5. The in vitro enzymatic assay results indicated that four compounds (2, 4, 10 and 37) showed PRMT5 inhibitory activity, while 4 and 10 displayed the most potent activity with IC50 values of 8.1 ± 1.1 and 6.5 ± 0.6 µM, respectively. The inhibitory activity results of 20 extra analogs of 4 further confirmed the potency of this scaffold. As expected, compounds 4 and 10 exhibited moderate anti-proliferative activity against mantle cell lymphoma Jeko-1 and leukemia cell MV4-11. Besides, Western blot assay results showed that 4 could reduce the H4R3me2s level in a dose-dependent manner, indicating that it could inhibit the activity of PRMT5 in cellular context. Detailed interactions between 4 and PRMT5 were characterized by binding mode analysis through molecular docking. The compounds discovered in this study will inspire medicinal chemists to further explore this series of PRMT5 inhibitors.

Synthesis, Anticancer Activity and Molecular Modeling Studies of Novel Chalcone Derivatives Containing Indole and Naphthalene Moieties as Tubulin Polymerization Inhibitors.

Abstract: Eighteen novel chalcone derivatives containing indole and naphthalene moieties (2-19) were synthesized and characterized by 1H-NMR, 13C-NMR and high resolution (HR)-MS spectra. All compounds were evaluated for their in vitro cytotoxic potential against human hepatocellular carcinoma (HepG2), human colon carcinoma (HCT116) and human breast adenocarcinoma (MCF-7) cell lines. Among them, compound 2, 3, 4 and 7 showed potent activities against tested cancer cell lines. More significantly, compound 7 exhibited the most potent cytotoxic activity against HepG2, HCT116 and MCF-7 with IC50 values of 0.65, 1.13 and 0.82 µM, respectively. Furthermore, flow cytometry analysis indicated that compound 7 arrested cancer cells in G2/M phase. The compound 7 also displayed significant inhibition of tubulin polymerization (IC50 = 3.9 µM). Finally, molecular docking studies were performed to explore the possible interactions between compound 7 and tubulin binding pockets.

Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity.

Abstract: Biliary lipids consist mainly of bile salts, phospholipids and cholesterol, which form mixed micelles and vesicles. Bile salts play various physiological roles but have damaging effects on cell membranes due to their detergent properties. The cytotoxicity of bile salts on hepatocytes leads to liver injuries and is largely determined by the bile salt species, the concentrations of bile salts, phospholipids and cholesterol, and the lipid composition of cell membranes. In bile, monomers and simple micelles of bile salts coexist with mixed micelles and vesicles in dynamic equilibrium, and contribute to the cytotoxicity on hepatocytes. The ATP-binding cassette (ABC) transporter family members, ABCB11, ABCB4 and ABCG5/ABCG8, mediate the biliary secretion of bile salts, phospholipids and cholesterol, respectively. Mutations in ABCB4 result in severe cholestatic diseases, and the biliary phospholipids are necessary for the attenuation of bile salt cytotoxicity. On the other hand, cholesterol reverses the cytoprotective effects of phospholipids against bile salts. In addition, phosphatidylethanolamine N-methyltransferase increases the cell resistance to bile salts by changing the phospholipid composition and structures of the apical membranes. In this review, we focus on the molecular mechanisms for the protection of hepatocytes against bile salt cytotoxicity. Further understanding of these mechanisms will help to develop new therapeutic strategies for cholestatic liver diseases.

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein.

Abstract: Chromosomal translocation occurs in some cancer cells, resulting in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate expression of the BCR-ABL protein. Recently, we have devised a protein knockdown system by hybrid molecules named Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER). This system is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins. In this review, we describe the development of SNIPER against BCR-ABL, and discuss the features and prospect for treatment of CML.

Development of Boron-Cluster-Based Progesterone Receptor Antagonists Bearing a Pentafluorosulfanyl (SF 5 ) Group.

Abstract: The progesterone receptor (PR) plays an important role in various physiological processes, especially in the female reproductive system, and abnormalities of PR function are associated with several diseases, including some types of cancer. Non-steroidal PR ligands are of interest as candidate drugs for treatment of PR-related diseases without the serious adverse effects that may be caused by steroidal ligands. For the development of non-steroidal PR ligands, both a hydrophobic backbone and a polar functional group corresponding to the 3-carbonyl group of progesterone, which interacts with Gln725 and Arg766 of the PR-ligand binding domain, are critically important. We previously showed that carborane is a useful hydrophobic pharmacophore for PR antagonists, and in this work, we introduced the pentafluorosulfanyl (SF5) group as a novel polar functional group of carborane-based non-steroidal PR antagonists. All the synthesized SF5-containing carborane derivatives exhibited PR-antagonistic activity at micromolar or submicromolar concentration. Among them, compounds 11 are potent progesterone antagonists with submicromolar IC50 values.

Field Survey of Glycyrrhiza Plants in Central Asia (5). Chemical Characterization of G. bucharica Collected in Tajikistan.

Abstract: One triterpene and five triterpene glycosides, including four new compounds, have been identified in the underground parts of Glycyrrhiza bucharica, which was shown to be closely related to Glycyrrhizin-producing Glycyrrhiza species, G. uralensis, G. glabra and G. inflata, based on their chloroplast rbcL sequences. Two known compounds were identified squasapogenol and macedonoside C. The structures of four new compounds, bucharosides A, B, C, and D, were determined to be 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucuronopyranosyl-(1→2)-β-D-glucuronopyranosyl-22-O-α-L-rhamnopyranosyl squasapogenol, 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucuronopyranosyl-(1→2)-β-D-glucuronopyranosyl-macedonic acid, 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucuronopyranosyl-(1→2)-β-D-glucuronopyranosyl-squasapogenol, and 22-O-α-L-rhamnopyranosyl squasapogenol, respectively. Contents of these triterpene glycosides were less than 0.5% of dry weight, and no main saponin, like glycyrrhizin or macedonoside C found in other Glycyrrhiza species, was found in the underground parts of G. bucharica.

Design and Synthesis of Triazole-Phthalimide Hybrids with Anti-inflammatory Activity

Abstract: Phthalimido-alkyl-1H-1,2,3-triazole derivatives 3a-d and 4a-d were efficiently synthesized using 1,3-dipolar cycloaddition reaction. Anti-inflammatory activity and toxicity studies were performed. The results demonstrated that all the tested compounds reduced carrageenan-induced paw edema and indicated no lethality for toxicity against Artemia salina and acute toxicity in vivo (LD50 up to 1 g kg -1). Furthermore, the structure of phthalimide linked to phenyl group proved to be more active than the compounds containing benzothiazole moiety. Structural modifications such as removal of the phthalimide group and subsequent acetylation, to exemplify a non-cyclic amide, demonstrate that the phthalimide and triazole moieties are important for design of potent candidates with anti-inflammatory drug proprieties. Docking into the cyclooxygenase-2 (COX-2) confirms the importance of the phthalimide and triazole groups in the anti-inflammatory activity. The histopathological studies showed that the compounds 3a-d and 4a-d did not cause serious pathological lesions liver or kidneys.

Development of Diagnostic and Therapeutic Probes with Controlled Pharmacokinetics for Use in Radiotheranostics.

Abstract: The word "theranostics," a portmanteau word made by combining "therapeutics" and "diagnostics," refers to a personalized medicine concept. Recently, the word, "radiotheranostics," has also been used in nuclear medicine as a term that refer to the use of radioisotopes for combined imaging and therapy. For radiotheranostics, a diagnostic probe and a corresponding therapeutic probe can be prepared by introducing diagnostic and therapeutic radioisotopes into the same precursor. These diagnostic and therapeutic probes can be designed to show equivalent pharmacokinetics, which is important for radiotheranostics. As imaging can predict the absorbed radiation dose and thus the therapeutic and side effects, radiotheranostics can help achieve the goal of personalized medicine. In this review, I discuss the use of radiolabeled probes targeting bone metastases, sigma-1 receptor, and αVβ3 integrin for radiotheranostics.

Metal-Free Oxidative Cross-Coupling Reaction of Heteroaromatic and Related Compounds.

Abstract: The biary unit having heteroatom as important scaffolds widely exist in a large number of biologically active compounds and functional organic molecules. Since the cross-coupling is a useful synthetic method for constructing biaryl and heterobiaryl structures, the development of novel cross-coupling methods has been studied intensively. The oxidative biaryl coupling reaction of aromatic compounds having heteroatoms is an attractive method since they do not require the prefunctionalization of arenes. This report describes recent advances in hypervalent iodine(III) induced metal-free synthesis of biaryls having heteroatoms.

YiQi Tongluo Granule against Cerebral Ischemia/Reperfusion Injury in Rats by Freezing GluN2B and CaMK II through NMDAR/ERK1/2 Signaling.

Abstract: Yiqi Tongluo Granule (YQTL) is a kind of proprietary Chinese medicine, manufactured by China Shineway Pharmaceutical Group Ltd., under the authority of China Food and Drug Administration (CFDA) treating cardiovascular and cerebrovascular diseases such as ischemic stroke in China, however the underlying mechanism of YQTL on treating ischemic stroke has not been revealed. This study is aimed to evaluate the protective effect of YQTL on cerebral ischemia/reperfusion (I/R) injury and inquire into its underlying mechanisms. Cerebral I/R injury was induced by occluding the middle cerebral artery for 2 h followed by 24 h reperfusion. And regional cerebral flow was monitored by Laser Doppler flow during ischemia phase. The infarct volume was evaluated by Triphenyte-trazolium chloride staining. The protective effects of YQTL were assessed by a number of parameters, including neurological scores, regional cerebral blood flow, pathological changes of neuron in hippocampuses and hippocampus calcium level. The proteins of extracellular signal-regulated kinase (ERK), N-methyl D-aspartate receptor subtype 2B (GluN2B) and p-calcium-dependent protein kinaseII (CaMKII) response were assayed by Western blotting. I/R caused significant change in neurological deficit scores, regional cerebral flow and infarct volume. However results in YQTL groups and Nimodipine Tablets (NMDP) group were reversed. Subsequently YQTL reduced I/R-induced calcium influx. Results of hematoxylin-eosin staining manifested that YQTL significantly improved neuronal injury after I/R in rats. Meanwhile, microdialysis data demonstrated that extracellular glutamate was increased in the striatum during ischemia reperfusion, which was reduced by YQTL. YQTL and mitogen-activated protein extracellular kinase (MEK) inhibitor suppressed the I/R-mediated over-expression of GluN2B, p-ERK, ERK and p-CaMKII proteins expression. Putting these together, our results suggest that YQTL played a neuroprotective role in cerebral I/R injury, which might be exerted by inhibiting the excitotoxicity and expression of GluN2B, p-CaMKII and MEK/ERK signal pathway.

Nanodiscs for Structural Biology in a Membranous Environment.

Abstract: The structures of many membrane proteins have been analyzed in detergent micelles. However, the environment of detergent micelles differs somewhat from that of the lipid bilayer, where membrane proteins exhibit physiological functions. Therefore, a more membrane-like environment has been awaited for structural analysis of membrane proteins. Nanodiscs are "hockey-puck"-shaped lipid bilayer particles that distribute in a monodispersed manner in aqueous solution. We review how nanodiscs or protein-reconstituted nanodiscs are prepared and how they are utilized to analyze protein structure, dynamics, and interactions with lipid molecules using solution NMR and cryo-electron microscopy.

Preparation of Cocoa Powder-Containing Orally Disintegrating Tablets of Rebamipide (Rebamipide Chocolet) and Evaluation of Their Clinical Palatability.

Abstract: Orally disintegrating tablets (ODTs), which are administered without water, are beneficial for elderly patients and patients with dysphagia. Masking the unpleasant taste of a drug is an important factor associated with adherence of patients consuming ODTs. We prepared cocoa powder-containing ODTs of bitter-tasting rebamipide (rebamipide chocolet) and evaluated their clinical palatability. We prepared rebamipide ODTs by adding a sweetener and 0, 2.5, 5, and 10% cocoa powder (Ch0-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs, respectively). Rebamipide ODTs without cocoa powder and sweetener were used as controls (Cont-ODTs). We performed a gustatory sensation test in 30 healthy adult volunteers. We used the 100-mm visual analog scale (VAS) to evaluate bitterness, sweetness, scent, and overall palatability of the ODTs. The acceptability of each ODT was evaluated on a 5-point scale. Compared to Cont-ODTs, Ch0-ODTs showed no significant improvement in the VAS score for bitterness, scent, and overall palatability during disintegration. However, compared to Cont-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs showed an improvement in all items evaluated using the VAS. In particular, Ch2.5-ODTs showed a significant improvement compared to the Cont-ODTs in the VAS score of all items. Evaluation on a 5-point scale indicated that Ch2.5-ODTs and Ch10-ODTs had the highest acceptability. We prepared rebamipide chocolet with excellent palatability properties, which could not be achieved using a sweetener alone, by using the combination of a sweetener and cocoa powder as a new agent for masking bitterness. Our results indicate that cocoa powder may be used as a taste-masking agent in ODTs.

Effect of Particle–Wall Interaction and Particle Shape on Particle Deposition Behavior in Human Respiratory System

Abstract: Dry powder inhalation (DPI) has attracted much attention as a treatment for respiratory diseases owing to the large effective absorption area in a human respiratory system. Understanding the drug particle motion in the respiratory system and the deposition behavior is necessary to improve the efficiency of DPI. We conducted computer simulations using a model coupling a discrete element method and a computational fluid dynamics method (DEM-CFD) to evaluate the particle deposition in human respiratory system. A simple artificial respiratory model was developed, which numerically investigated the effect of particle properties and inhalation patterns on the particle deposition behavior. The DEM-CFD simulations demonstrated that the smaller- and lower-density particles showed higher reachability into the simple respiratory model, and the particle arrival ratio to the deep region strongly depended on the aerodynamic diameter. The particle arrival ratio can be described as an exponential function of the aerodynamic diameter. Furthermore, the exponential relationship between the particle reachability into the depth of the simple respiratory model and the aerodynamic diameter predicted the particle aerodynamic diameter based on the required reachability. The particle shape also had an impact on the particle deposition behavior. The rod-like particles with a larger aspect ratio indicated higher reachability into the depth of the simple respiratory model. This was attributed to the high velocity motion of the particles whose long axis was in the direction of the deep region.

A Probe for Fluorescence Detection of the Acetylcholinesterase Activity Based on Molecularly Imprinted Polymers Coated Carbon Dots.

Abstract: This paper presents a new probe for fluorescence detection of the acetylcholinesterase (AChE) activity based on molecularly imprinted polymer (MIP) coated carbon dots (C-dots) composite. The C-dots were hydrothermally synthesized with grafted silica surface and sealed with molecularly imprinted polymers in silica pores (MIP@C-dots) in situ. Removed the original template molecules, the MIP@C-dots composite exhibits quite high selectivity for acetylthiocholine (ACh). With AChE, its substrate ACh will be hydrolyzed into thiocholine and the fluorescence signals exhibit a dramatic decrease at 465 nm, Under optimal conditions, the fluorescent probe shows sensitive responses to AChE in the range of 0.01-0.6 mU/mL. The detection limits of AChE are as low as 3 µU/mL. These experiments results validate the novel fluorescent probe based on MIP@C-dots composite, paving a new way to evaluation of AChE activity and Screening inhibitors.

Bitterness-Masking Effects of Different Beverages on Zopiclone and Eszopiclone Tablets.

Abstract: The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

Quality Assessment of Medicinal Product and Dietary Supplements Containing Vitex agnus-castus by HPLC Fingerprint and Quantitative Analyses

Abstract: In this study, we aimed to evaluate the quality of 11 products sold in Japan (one medicinal product and 10 dietary supplements) containing/claiming to contain chasteberry extract (fruit of Vitex agnus-castus L.) using HPLC fingerprint (15 characteristic peaks), quantitative determination of chemical marker compounds, and a disintegration test. The HPLC profile of the medicinal product was similar to that of the reference standard of V. agnus-castus fruit dry extract obtained from European Directive for the Quality of Medicines (EDQM), whereas the profiles of some dietary supplements showed great variability, such as different proportions of peaks or lack of peaks. Results of the principal component analysis of the fingerprint data were consistent with those of the HPLC profile analysis. The contents of two markers, agnuside and casticin, in dietary supplements showed wide variability; this result was similar to that achieved with the HPLC fingerprint. In particular, agnuside and/or casticin was not detected in two dietary supplements. Furthermore, one dietary supplement was suspected to be contaminated with V. negundo, as evidenced from the results of agnuside to casticin ratio and assay of negundoside, a characteristic marker of V. negundo. Results of the disintegration test showed poor formulation quality of two dietary supplements. These results call attention to the quality problems of many dietary supplements, such as incorrect or poor-quality origin, different contents of the active ingredient, and/or unauthorized manufacturing procedures.

A 3D-QSAR Analysis of CDK2 Inhibitors Using FMO Calculations and PLS Regression.

Abstract: We report a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of CDK2 inhibitors using fragment molecular orbital (FMO) calculations and partial least squares (PLS) regression. In our analysis, fragment binding energies of individual amino acids and fragment binding energy of a single ligand in a protein-ligand complex are evaluated by FMO calculations and used as descriptors in PLS regression to estimate biological activities of the ligands. The analysis was applied to the system of CDK2 protein and its inhibitors and the effectiveness of the method was tested. Application of the 3D-QSAR model demonstrated that it offered good predictive ability and was able to predict not only biological activity of ligands but also identify important amino acid residues which could be targeted in order to improve ligand activity.

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).

Abstract: Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.

Design, Synthesis and Biological Evaluation of Novel Benzoylimidazole Derivatives as Raf and Histone Deacetylases Dual Inhibitors.

Abstract: In recent studies, combinations of histone deacetylases (HDACs) inhibitor with kinase inhibitor showed additive and synergistic effects. BRafV600E as an attractive target in many diseases treatments has been studied extensively. Herein, we present a novel design approach though incorporating the pharmacophores of BRafV600E inhibitor and HDACs inhibitor in one molecule. Several synthesized compounds exhibited distinct BRafV600E and HDAC1 inhibitory activities. The representative dual Raf/HDAC inhibitor, 7a, showed better antiproliferative activities against A549 and SK-Mel-2 in cellular assay than SAHA and sorafenib, with IC50 values of 9.11 µM and 5.40 µM, respectively. This work may lay the foundation for the further development of dual Raf/HDAC inhibitors as potential anticancer agents.