| Co-Investigator(Kenkyū-buntansha) |
GOTO Satoru Faculty of Pharmaceutical Sciences, University of Tolushima, Assistant Professor, 薬学部, 助手 (50253232)
HORI Hitoshi Faculty of Engineering, University of Tokushima, Professor, 工学部, 教授 (90119008)
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| Research Abstract |
Biscoclaurine type alkaloids (cepharanthine, tetrandrine and isotetrandrine) modified the hormonal activity through the modification of cell membrane condition. We simulated the structure of these alkaloids using molecular dynamics, and we obtained the structural feature of them. From their molecular features, we designed and synthesized the steric hindered phenol "TX-1123" and the 2-nitromidazole compound "TX-1877". These compounds markedly modified the hormonal action. Indeed, TX-1123 and TX-1877 modulated the β-agonist induced-fatty acid synthesis with insulin in rat white adipocytes. Insulin-involved fatty acid synthesis was dose-dependently suppressed by TX-1123, and synthesized fatty acid was increased. In contrast, TX-1877 dose-dependently promoted this insulin-involved fatty acid metabolism, and decreased the amounts of synthesized fatty acid. Moreover, we created the stereohydrophobic parameter "dGW" obtained by semiempirical molecular orbital calculation to apply the structure-activity relationship analysis. This parameter reflected the three-dimensional structure of target compound, such as stereoisoform, and it was very useful for drug design. We analyzed the apoptotic inducer brefeldin A (BFA) using dGW, and designed and synthesized the 4-epi-BFA. The 4-epi-BFA was the stereoisomer of BFA at 4-hydoxy group, and it had no apoptotic activity. Now we are investigating the new type anti-cancer agents, which modulate the apoptosis of tumor cells.
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