アセチレンスピロアセタールエノールエーテル化合物群の合成研究

金沢大学理工研究域キク科植物は民間薬として古くより活用されてきた植物である。同植物から生理活性成分が数多く報告されているが、中でもスピロアセタール構造、エノールエーテル構造及び(E)-エンジイン構造を有する一連の化合物群は、僅かな構造の差異により脳、消炎、鎮痙作用から抗腫瘍活性と、幅広い生理作用を有することが知られている。しかしながら、これら化合物は天然から得られる量が僅かなため、十分な活性評価がなされていない。研究者は、これら天然物の化学合成による大量供給を目的として本研究を遂行し以下の結果を得た。一連の化合物群の合成を行うにあたり、まず抗腫瘍活性を有し、スピロアセタール構造上にエポキシ環を有するAL-2を初期標的化合物に設定し、効率的合成法の開発を検討した。AL-2のエポキシ部分が酒石酸由来の二つの水酸基から誘導可能であることに着目し、市販品として容易に入手可能なL-酒石酸ジエチルを出発物質として、数工程で環化反応前駆体である三重結合を有するδケトアルコール体を合成した。環化反応前駆体をMeOH中、CO気流下,触媒量のPd_2(dba)_3と処理したところ、スピロ環構築とメチルエステル部の形成が進行し、ジオキサスピロ化合物の合成に成功した。続いて、メチルエステル部をジイン体へと誘導し、L-酒石酸由来の水酸基をエポキシ構造へ変換し、AL-2の最初の全合成を達成した。加えて、開発した合成経路を基盤とし、4種の類縁化合物の合成も達成した。研究課題/領域番号:15790007, 研究期間(年度):2003 – 2004出典：「アセチレンスピロアセタールエノールエーテル化合物群の合成研究」研究成果報告書　課題番号15790007（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-15790007/)を加工して作

キク科植物由来(-)-ichthyothereol,(-)-AL-2及びそれら関連天然物の最初の全合成

取得学位：博士(薬学)，学位授与番号：博乙第316号，学位授与年月日：平成19年3月22

Effect of a 2.45-GHz radiofrequency electromagnetic field on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells

The potential public health risks of radiofrequency (RF) fields have been discussed at length, especially with the use of mobile phones spreading extensively throughout the world. In order to investigate the properties of RF fields, we examined the effect of 2.45-GHz RF fields at the specific absorption rate (SAR) of 2 and 10 W/kg for 4 and 24 h on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells. Neutrophil chemotaxis was not affected by RF-field exposure, and subsequent phagocytosis was not affected either compared with that under sham exposure conditions. These studies demonstrated an initial immune response in the human body exposed to 2.45-GHz RF fields at the SAR of 2 W/kg, which is the maximum value recommended by the International Commission for Non-Ionizing Radiation Protection (ICNIRP) guidelines. The results of our experiments for RF-field exposure at an SAR under 10 W/kg showed very little or no effects on either chemotaxis or phagocytosis in neutrophil-like human HL-60 cells

Expression of heat shock proteins in human fibroblast cells under magnetic resonant coupling wireless power transfer

Since 2007, resonant coupling wireless power transfer (WPT) technology has been attracting attention and has been widely researched for practical use. Moreover, dosimetric evaluation has also been discussed to evaluate the potential health risks of the electromagnetic field from this WPT technology based on the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. However, there has not been much experimental evaluation of the potential health risks of this WPT technology. In this study, to evaluate whether magnetic resonant coupling WPT induces cellular stress, we focused on heat shock proteins (Hsps) and determined the expression level of Hsps 27, 70 and 90 in WI38VA13 subcloned 2RA human fibroblast cells using a western blotting method. The expression level of Hsps under conditions of magnetic resonant coupling WPT for 24 h was not significantly different compared with control cells, although the expression level of Hsps for cells exposed to heat stress conditions was significantly increased. These results suggested that exposure to magnetic resonant coupling WPT did not cause detectable cell stress

In vitro evaluation of genotoxic effects under magnetic resonant coupling wireless power transfer

Wireless power transfer (WPT) technology using the resonant coupling phenomenon has been widely studied, but there are very few studies concerning the possible relationship between WPT exposure and human health. In this study, we investigated whether exposure to magnetic resonant coupling WPT has genotoxic effects on WI38VA13 subcloned 2RA human fibroblast cells. WPT exposure was performed using a helical coil-based exposure system designed to transfer power with 85.4% efficiency at a 12.5-MHz resonant frequency. The magnetic field at the positions of the cell culture dishes is approximately twice the reference level for occupational exposure as stated in the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. The specific absorption rate at the positions of the cell culture dishes matches the respective reference levels stated in the ICNIRP guidelines. For assessment of genotoxicity, we studied cell growth, cell cycle distribution, DNA strand breaks using the comet assay, micronucleus formation, and hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene mutation, and did not detect any significant effects between the WPT-exposed cells and control cells. Our results suggest that WPT exposure under the conditions of the ICNIRP guidelines does not cause detectable cellular genotoxicity

Effect of an intermediate-frequency magnetic field of 23 kHz at 2 mT on chemotaxis and phagocytosis in neutrophil-like differentiated human HL-60 cells.

Public concerns about potential health risks of intermediate-frequency (IF) electromagnetic fields are increasing, especially as the use of induction-heating cooktops has spread extensively in Japan and Europe. In order to investigate the properties of IF electromagnetic fields, we examined the effect of exposure to a 23-kHz IF magnetic field of 2 mT for 2, 3, or 4 h on neutrophil chemotaxis and phagocytosis using differentiated human HL-60 cells. Compared with sham exposure, exposure to the IF magnetic field had no effect on neutrophil chemotaxis or phagocytosis. Previous studies demonstrated that exposure to a 23-kHz IF magnetic field of 2 mT (about 74-times the maximum value recommended by the International Commission for Nonionizing Radiation Protection guidelines) may affect the first-line immune responses in humans. To our knowledge, this is the first study to evaluate the effects of IF magnetic fields on cellular immune responses. We found that exposure to an IF magnetic field of 2 mT has minimal if any effect on either the chemotaxis or phagocytic activity of neutrophil-like human HL-60 cells

Alteration of gene expression by exposure to a magnetic field at 23 kHz is not detected in astroglia cells.

The increasing use of induction heating (IH) cooktops has roused public concern in Japan and Europe regarding potential health effects. The purpose of this study was to evaluate the effects of exposure to a magnetic field at 23 kHz (which is the maximum output power frequency of most IH cooktops) on gene expression in a human-fetus-derived astroglia cell line, SVGp12. The cells were exposed to the magnetic field at 2 mTrms [which is approximately 74 times higher than the reference level in the most recent International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines], for 2, 4 and 6 h, using a previously reported exposure system. Gene expression was evaluated using an Agilent cDNA microarray. We did not detect any significant effects of the magnetic field on the gene expression profile. On the contrary, heat treatment at 43°C for 2 h used as a positive control significantly affected gene expression, including inducing heat shock proteins, which indicated that our protocol for microarray analysis was appropriate. From these results, we conclude that exposure of human-fetus-derived astroglia cells to an intermediate-frequency magnetic field at 23 kHz and 2 mTrms for up to 6 h does not induce detectable alteration of gene expression

Recovery kinetics of micronucleus formation by fractionated X-ray irradiation in various types of human cells

High-dose ionizing radiation is sufficient for breaking DNA strands, leading to cell death and mutations. By contrast, the effects of fractionated ionizing radiation on human-derived cells remain unclear. To better understand the genotoxic effects of fractionated ionizing radiation, as well as the cellular recovery rate, we investigated the frequency of micronucleus (MN) formation in various types of human cells. We irradiated cells with fractionated X-ray doses of 2 Gy at a rate of 0.0635 Gy/min, separated into two to eight smaller doses. After irradiation, we investigated the frequency of MN formation. In addition, we investigated the rate of decrease in MN frequency after irradiation with 1 or 2 Gy X-rays at various recovery periods. Fractionated irradiation decreased MN frequency in a dose-dependent manner. When the total dose of X-rays was the same, the MN frequencies were lower after fractionated X-ray irradiation than acute irradiation in every cell type examined. The rate of MN decrease was faster in KMST-6 cells, which were derived from a human embryo, than in the other cells. The rate of MN decrease was higher in cells exposed to fractionated X-rays than in those exposed to acute irradiation. Recovery rates were very similar among cell lines, except in KMST-6 cells, which recovered more rapidly than other cell types