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Chem Pharm Bull [journal]
- Design and synthesis of 2-nitroimidazoles with variable alkylating and acylating functionality. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):301-3.
The synthesis of a small series of 2-nitroimidazoles in which the β-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C1.6 values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.
- Two new ring-contracted congeners of rhizopodin illustrate significance of the ring moiety of macrolide toxins on the actin disassembly-mediated cytotoxicity. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):294-300.
Two new cytotoxic dilactones, bisisorhizopodin (1) and isorhizopodin (2), together with known divalent actin depolymerizer rhizopodin (3), were isolated from the culture broth of a myxobacterium Myxococcus stipitatus. Spectroscopic analyses established that 1 and 2 are doubly and singly acyl-migrated isomers of 3, respectively, and comparison of their cytotoxicity revealed gradual decrease in the activity as the size of the ring contracted. Because the side chains of macrolide toxins uniformly block the contact between the actin protomers, the present result demonstrates substantial contribution of structurally diverse rings to the affinity of macrolide toxins for its target protein.
- Three New Lignan Glycosides with IL-6 Inhibitory Activity from Akebia quinata. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):288-93.
Three new lignan glycosides, akeqintoside A [(7S,8S)-7,8-dihydro-8-hydroxymethyl-7-(4-hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol 2'-O-β-D-glucopyranoside] (1), akeqintoside B [(7R,8R)-7,8-dihydro-8-hydroxymethyl-7-(4-hydroxy-3-methoxyphenyl)-1'-(9'-methoxy-7'-propenyl) benzofuran 2'-O-β-D-glucopyranoside] (2), and akequintoside C [7R*,8R*-dihydroxy-7-(4-hydroxy-3-methoxyphenyl)-glycerol 9-O-β-D-(6'-O-caffeoyl)-glucopyranoside] (3) were isolated from Akebia quinata along with five known compounds, syringin (4), vanilloloside (5), salidroside (6), 3,4-dihydroxyphenylethyl alcohol 8-O-β-D-glucopyranoside (7), and calceolarioside B (8). The structures of the compounds were identified based on one dimensional (1D)- and 2D-NMR, including (1)H-(1)H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and nuclear Overhauser effect spectroscopy (NOESY) spectroscopic analyses. The inhibitory activity of these isolated compounds against interleukin-6 (IL-6) production in tumor necrosis factor-alpha (TNF-α) stimulated MG-63 cells was also examined.
- Effect of the compaction platform on the densification parameters of tableting excipients with different deformation mechanisms. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):281-7.
Several compaction models have been attempted to explain the compression and compaction phenomena of excipients. However, the resulting parameters could be influenced by the compaction platform such as dwell time, compact mass, geometry and type of material. The goal of this study is to assess the effect of these variables on the densification parameters obtained from key models such as Heckel, non-linear Heckel, Kawakita, Carstensen, and Leuenberger. The relationship among the parameters derived was determined by employing a Principal Component Analysis. Results indicated that factors such as compact geometry, consolidation time and compact mass had a negligible impact on parameters such as tensile strength, yield pressure and compressibility. On the contrary, the excipient type had the largest influence on these parameters. Further, the Leuenberger (γ) and Carstensen (f) parameters were highly correlated and related to the excipient deformation mechanism. Sorbitol and PVP-k30 were the most highly compactable excipients and were characterized for having a low yield pressure (Py), compressibility (a), and critical porosity (εc). The magnitude of these parameters was highly dependent on the consolidation behavior of each material.
- Efficient delivery and distribution in skin of chlorogenic Acid and resveratrol induced by microemulsion using sucrose laurate. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):274-80.
To achieve efficient skin delivery of polyphenols, we prepared a novel oil-in-water (o/w)-type microemulsion (MESL) using sucrose laurate as a surfactant and ethanol, isopropyl myristate and water as other components. We examined its usefulness by in vitro studies on skin delivery of chlorogenic acid and resveratrol as hydrophilic and hydrophobic polyphenols using Yucatan micropig skin, and also examined the difference in the distribution of these polyphenols in skin. MESL significantly improved skin incorporation of these polyphenols at all time points examined (6, 20, 40 h) in the epidermis and at 20 and 40 h in the dermis, compared with the microemulsion using Tween 80 as a surfactant component (MEK), although the solubilization capacity of MESL was lower than that of MEK. Using MESL, the incorporation amount in the dermis of each polyphenol increased with time, while the amount in the epidermis was almost constant during the time examined. Incorporation efficiencies into skin of chlorogenic acid and resveratrol induced by MESL at 40 h after application were about 6-fold and 19-fold higher in the epidermis and 3.5-fold and 15-fold higher in the dermis, respectively, than those by MEK. The increase was more prominent for resveratrol. Hydrophilic chlorogenic acid was distributed slightly more in the epidermis, while hydrophobic and smaller-molecular-weight resveratrol was mainly distributed in the dermis. These findings suggest that MESL could be a promising vehicle for the efficient skin delivery of chlorogenic acid and resveratrol, especially for resveratrol to the dermis.
- New Cassane-Type Diterpenoids of Caesalpinia echinata (Leguminosae) Exhibiting NF-κB Inhibitory Activities. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):267-73.
Seven new cassane-type diterpenoids, echinalides A-G (1-7), were isolated from the stem of Caesalpinia echinata LAM. (Leguminosae). The structures were established on the basis of their chemical properties and spectroscopic evidence, including two dimensional (2D)-NMR analysis. These compounds were assessed for inhibitory activity against nuclear factor κB (NF-κB). Echinalides C and D, in particular, significantly inhibited NF-κB-responsive reporter gene expression at 5.0 µM, an effect almost equivalent to that of parthenolide, a known potent inhibitor of NF-κB.
- Cytotoxic Activity and DNA-Binding Properties of Isoeuxanthone Derivatives. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):260-6.
In this study, the interactions of different groups substituted isoeuxanthone derivatives with calf thymus DNA (ct DNA) were investigated by spectrophotometric methods and viscosity measurements. Results indicated that the xanthone derivatives could intercalate into the DNA base pairs by the plane of xanthone ring and the various substituents may influence the binding affinity with DNA according to the calculated quenching constant values. Furthermore, two tumor cell lines including the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) were used to evaluate the cytotoxic activities of xanthone derivatives by acid phosphatase assay. Analyses showed that the oxiranylmethoxy substituted xanthone exhibited more effective cytotoxic activity against the cancer cells than the other substituted xanthones. The effects on the inhibition of tumor cells in vitro agreed with the studies of DNA-binding.
- Diarylamines Incorporating Hexahydrophenalene or Octahydrobenzoheptalene as Retinoid X Receptor (RXR)-Specific Agonists. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):254-9.
Selective ligands for retinoic acid receptors (RARs) and for retinoid X receptors (RXRs) are required for both biological studies and therapeutic purposes. We have synthesized a series of diarylamines incorporating hexahydrophenalene or octahydrobenzoheptalene as a hydrophobic moiety and examined their activities towards RARs and RXRs. Most of these compounds showed agonistic activity towards RXRs, but were inactive towards RARs. These RXR-specific ligands showed synergistic activity in RARα,β ligand-induced terminal differentiation of leukemia cell line HL-60.
- A study on the adsorption of heavy metals by using raw wheat bran bioadsorbent in aqueous solution phase. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):247-53.
Raw wheat bran (R-WB) was used as a biomass adsorbent. The properties of R-WB were investigated. Moreover, the adsorption of cadmium and lead ions onto R-WB was evaluated. Adsorption equilibrium of cadmium and lead ions onto R-WB was achieved within 10 h, indicating that the adsorption followed a pseudo-second-order model rather than a pseudo-first-order kinetic model. The adsorption amount increased with increasing temperature. Correlation coefficient of the Langmuir equation is 0.999 for cadmium and 0.996 for lead ions, and that of the Freundlich equation is 0.994 for cadmium and 0.993 for lead ions. The negative ΔG value implied that the adsorption of cadmium and lead ions onto R-WB is a spontaneous process. The positive ΔS value indicated an increase in randomness at the solid-liquid interface. The optimal conditions for the adsorption column experiment were investigated (space velocity (SV) 2.2 1/h, linear velocity (LV) 0.1 m/h for cadmium; SV 6.51 1/h, LV 0.23 m/h for lead ions). Further, repeated adsorption-desorption of the cadmium and lead ions could be effected by using 0.01 mol/L HCl or 0.01 mol/L HNO3 solution. Consequently, polluted water could be successfully purified by using a column filled with this bioadsorbent.
- Monte Carlo Simulations on Atropisomerism of Thienotriazolodiazepines Applicable to Slow Transition Phenomena Using Potential Energy Surfaces by ab initio Molecular Orbital Calculations. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(3):229-37.
Compounds with a medium-sized flexible ring often show atropisomerism that is caused by the high-energy barriers between long-lived conformers that can be isolated and often have different biological properties to each other. In this study, the frequency of the transition between the two stable conformers, aS and aR, of thienotriazolodiazepine compounds with flexible 7-membered rings was estimated computationally by Monte Carlo (MC) simulations and validated experimentally by NMR experiments. To estimate the energy barriers for transitions as precisely as possible, the potential energy (PE) surfaces used in the MC simulations were calculated by molecular orbital (MO) methods. To accomplish the MC simulations with the MO-based PE surfaces in a practical central processing unit (CPU) time, the MO-based PE of each conformer was pre-calculated and stored before the MC simulations, and then only referred to during the MC simulations. The activation energies for transitions calculated by the MC simulations agreed well with the experimental ΔG determined by the NMR experiments. The analysis of the transition trajectories of the MC simulations revealed that the transition occurred not only through the transition states, but also through many different transition paths. Our computational methods gave us quantitative estimates of atropisomerism of the thienotriazolodiazepine compounds in a practical period of time, and the method could be applicable for other slow-dynamics phenomena that cannot be investigated by other atomistic simulations.