Wukirsari Tuti, Nishiwaki Hisashi, Nishi Kosuke, Sugahara Takuya, Akiyama Koichi, Kishida Taro, Yamauchi Satoshi
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan; South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan.
Bioorg Med Chem Lett. 2014 Sep 1;24(17):4231-5. doi: 10.1016/j.bmcl.2014.07.033. Epub 2014 Jul 29.
All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7'-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC50=16-20 μM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (-)-Kadangustin J showed stereospecific cytotoxic activity (IC50=47-67 μM). Since (R)-9'-fluoro derivative 23 was most potent (IC50=19 μM) among the corresponding fluoro stereoisomers, (R)-9'-alkyl derivatives were synthesized, hydrophobic 9'-heptyl derivative 27 showing highest activity (IC50=3.7 μM against HL-60, IC50=3.1 μM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9'-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay.
合成了1,7-开环-2,7'-环木脂素类的甲氧基丁烷和氟代丁烷的所有立体异构体，并将这些化合物的细胞毒性活性与丁烷和丁醇类化合物的所有立体异构体的细胞毒性活性进行了比较。丁烷型环木脂素的两种对映体均显示出比甲氧基型化合物更高的细胞毒性活性（IC50 = 16 - 20 μM），而丁醇型环木脂素的所有立体异构体均未观察到细胞毒性活性，然而，(-)-卡丹古斯汀J显示出立体特异性细胞毒性活性（IC50 = 47 - 67 μM）。由于(R)-9'-氟衍生物23在相应的氟代立体异构体中活性最强（IC50 = 19 μM），因此合成了(R)-9'-烷基衍生物，在本实验中，疏水性的9'-庚基衍生物27显示出最高活性（对HL-60的IC50 = 3.7 μM，对HeLa的IC50 = 3.1 μM）。在作用机制研究中观察到(R)-9'-庚基衍生物27可诱导Caspase 3和9介导的凋亡。DNA梯状条带分析也显示DNA降解为小片段。
