Oda T, Watanuki M, Sakakibara Y, Sato Y
Kyoritsu College of Pharmacy, Tokyo, Japan.
Biol Pharm Bull. 1995 Oct;18(10):1435-8. doi: 10.1248/bpb.18.1435.
We have previously reported the inhibitory effects of diethylstilbestrol (1) and optically active indenestrol derivatives on microtubule polymerization in vitro and their disruptive effect on cytoplasmic microtubules and cytotoxicity in cultured Chinese hamster V79 cells. In the present study, the cytotoxicities of (+-)-diethylstilbestrol oxide (2), (+)-, (-)- and (+-)-monomethyl ethers (4) of 2, (+-)-dimethyl ether (5) of 2, diethylstilbestrol pinacolone (3), E,E-dienestrol (6), Z,Z-dienestrol (7), meso-hexestrol (8), a mixture of (1R,1'S)4-hydroxyhexestrol and (1R,1'S)4'-hydroxyhexestrol (9), and the 4-hydroxy derivative (10) of diethylstilbestrol dimethyl ether were investigated in Chinese hamster V79 cells. The results indicated that the cytotoxic activity of 10 was the strongest of the compounds tested, although its activity was the almost same as that of 1. Moreover, as the activity of (-)-4 was greater than those of 2 and 1 monomethyl ethers, the effect of 4 on cytotoxic activities was elucidated. In conclusion, the present results indicate that the cytotoxic activities of hydroxylated metabolites are greater than those of each mother compound, although epoxidation of 1 leads to a product which can be broken down more readily than the parent compound.
我们之前曾报道过己烯雌酚（1）及旋光性茚雌酚衍生物对体外微管聚合的抑制作用，以及它们对培养的中国仓鼠V79细胞胞质微管的破坏作用和细胞毒性。在本研究中，检测了（±）-己烯雌酚氧化物（2）、2的（+）-、（-）-及（±）-单甲醚（4）、2的（±）-二甲醚（5）、己烯雌酚频哪酮（3）、E,E-双烯雌酚（6）、Z,Z-双烯雌酚（7）、内消旋己烷雌酚（8）、（1R,1'S）-4-羟基己烷雌酚与（1R,1'S）-4'-羟基己烷雌酚的混合物（9）以及己烯雌酚二甲醚的4-羟基衍生物（10）对中国仓鼠V79细胞的细胞毒性。结果表明，在所测试的化合物中，10的细胞毒性活性最强，尽管其活性与1几乎相同。此外，由于（-）-4的活性大于2和1的单甲醚，因此阐明了4对细胞毒性活性的影响。总之，目前的结果表明，羟基化代谢物的细胞毒性活性大于各自的母体化合物，尽管1的环氧化产生的产物比母体化合物更容易分解。
