| 著者：別形式 | Kurihara, Teruo / Mine, Hiroko / Satoh, Yoshimasa / Wakabayashi, Hidetsugu / Motohashi, Noboru / Sakagami, Hiroshi |
| 著者：所属(別形式） | Josai University, Faculty of Science, Department of Chemistry / Josai University, Faculty of Science, Department of Chemistry / Josai University, Faculty of Science, Department of Chemistry / Josai University, Faculty of Science, Department of Chemistry / Meiji Pharmaceutical University / Meikai University School of Dentistry |
| 抄録 | A structure-activity relationship of the cytotoxicactivity of tropolone derivatives was discussed, using theoreticalcalculations. In order to clearly divide the tropolones into twostructurally analogous groups, four different dipole moments(μG, μESP-G, μW and μESP-W) and heats of formation (ΔHf)of the tropolones [1-21] were calculated in the gas-phase andin water-solution by the conductor-like screeningmodel/parametric method 3 (COSMO/PM3). The cytotoxicactivities of the tropolones and 2-methoxytropones seem to berelated to the three QSAR parameters ΔΔHf, HOMO energy(EH) and μw. The cytotoxic activity of the five troponederivatives [17-21] might depend on the QSAR parametersΔΔHf, LUMO energy (EL) and μESP-G. The results of thepresent study suggest the applicability of theoretical calculations such as frontier molecular orbital, dipole momentsand ΔΔHf in the prediction of the cytotoxic activity oftropolone derivatives.Hinokitiol (compound [1] in Figure 1) and its relatedcompounds with a tropolone skeleton (1-3) have shown abroad spectrum of biological activities, includingantimicrobial (4), antifungal (5) and phytogrowth- inhibitoryactivities (6, 7), a cytotoxic effect on mammalian tumor cells(8, 9) and an inhibitory activity on catechol-O-methyltransferase(10) and metalloproteases (4). Hinokitiol acetatedid not show the cytotoxic activity (9), antimicrobial activityor metalloprotease inhibition (4), suggesting that thebiological effects of hinokitiol-related compounds mayresult from the metal chelation between the carbonyl groupat C-1 and the hydroxyl group at C-2 in the tropolone skeleton. However, no study of cytotoxicity induction bytropolone derivatives has yet been performed. Recently, thecytotoxicity of 27 tropolone derivatives against three humannormal cell lines and three human oral tumor cell lines wasreported by our group (11). The tropolone derivatives witha phenolic OH group, hinokitiol and its tosylate and methylethers, were found to have a relatively higher tumorspecificity. 5-Aminotropolone [6] showed the highest tumorspecificity, whereas 2-aminotropone [19] and its derivativesshowed little or no tumor specificity. 5-Aminotropolone [6]induced apoptotic cell death, as evidenced byinternucleosomal DNA fragmentation and caspase-3activation in human promyelocytic leukemic HL-60 cells(11). Based on a molecular orbital calculation using thephysicochemical property and the cytotoxic activity of thetropolone derivatives, the possible relationship between theelectronic structure and cytotoxic activity of tropolonederivatives was investigated. |
