| Co-Investigator(Kenkyū-buntansha) |
SATAKE Hiromu The University of Tokushima, Institute for Cooperative Research, Associate Profe, 地域共同研究センター, 助教授 (10124801)
KANESHINA Shoji The University of Tokushima, Faculty of Engineering, Professor, 工学部, 教授 (80035617)
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| Research Abstract |
We designed the following compounds : 1)salicylanilides, 2)thiodiazoles, 3)vitarmin K_1 epoxides, 4)disacchatide sulfates of steroids and triterpenoids(eg. glycyrrhizinic acid), 5)disaccharide(maltose and isomaltose)sulfates, 6)cyclodextrin-steroid complex as candidates of anti-ischemic drugs. Especially we studied the syntheses of new thiadiazole compounds such as TX-101-TX-109, their efftects against the respiratory activity in liver mitochondm in turtle as well as rat, and their in vivo anti-ischemic activity in mouse. We often used the UV detector for HPLC purchased by this grant detect our developed synthetic compounds for their isolation, analysis, and purification. As bioassay, we developed the aninmal model of anti-ischemic drug research using freshwater turtles(Mauremys japonica and Chineinys reevesii)as an animal anaerobe. The liver mitochondria were isolated from liver in turtle which was under hibernation, the RCI(Respiratory Control Index)of which was ca. 3. The mitochondrial function(oxygen consumption and ATP synthesis)was measured in our newly developed cell connected with high-sensitive sensors such as oxygen, pH, and membrane potential. TX-109 uncoupled the mitochondrial oxidative phosphorylation strongly[25nM(Vox max : 14natoms O/min/mg protein)]. This concentration of uncoupling activity in turtle liver mitochondria was similar, but its rate of oxygen consumption at this state was slower, in comparison with those in rat[TX-109 : 45nM(Vox max : 340natoms O/min/mg protein)]. These thiodiazole derivatives TX-101-109 showed weak anti-ischemic activities in vivo at the concentration of l00mg/kg i. p. We approached to develop the animal model using turtle live mitochondria and apply to the development of antiischemic drugs.
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