Sangjun Sunisa, de Jong Esther, Nijmeijer Sandra, Mutarapat Thumnoon, Ruchirawat Somsak, van den Berg Martin, van Duursen Majorie B M
Asian Institute of Technology, Mahidol University, Bangkok, Thailand.
Toxicol Lett. 2009 Apr 25;186(2):115-22. doi: 10.1016/j.toxlet.2009.01.017. Epub 2009 Jan 20.
In our present study, 12 new cis-stilbene derivatives (CRI-1-CRI-13) related to VIOXX((R)) were synthesized and studied for their inhibitory effects on cell cycle progression and anti-estrogenicity in human adenoma breast cancer MCF-7 cells. Based on the different substituents in the cis-stilbene molecule, we studied a possible structure activity relationship (SAR) for the inhibition of the cell cycle, cytotoxicity and (anti-) estrogenicity. The results showed that some cis-stilbenes have a pronounced effect on cell cycle distribution. CRI-5, 7, 10 and 12 caused an arrest of G2/M phase and reduction of G1/S phase in all tested doses (1-50 microM). In addition, some of these cis-stilbenes, have a moderate anti-estrogenic effect around 10 microM. Based on these results a preliminary SAR for cis-stilbene derivatives is suggested in which the presence and position of methoxy or thiomethoxy groups play an essential role in this cell cycle arrest. For this substitution on the para position of the left aromatic ring appears to be a prerequisite. However, the SAR for anti-estrogenicity appears to be different, but experimental information was too limited to define a possible SAR. In conclusion, our study shows that some synthetic cis-stilbene related to VIOXX might have chemopreventive properties that can effectively interfere with the cell cycle distribution of breast tumor cells.
在我们目前的研究中，合成了12种与万络（R）相关的新型顺式芪衍生物（CRI-1 - CRI-13），并研究了它们对人乳腺腺癌MCF-7细胞的细胞周期进程抑制作用和抗雌激素活性。基于顺式芪分子中不同的取代基，我们研究了抑制细胞周期、细胞毒性和（抗）雌激素活性的可能的构效关系（SAR）。结果表明，一些顺式芪对细胞周期分布有显著影响。CRI-5、7、10和12在所有测试剂量（1 - 50 microM）下均导致G2/M期阻滞和G1/S期减少。此外，其中一些顺式芪在10 microM左右具有中等程度的抗雌激素作用。基于这些结果，提出了顺式芪衍生物的初步构效关系，其中甲氧基或硫代甲氧基的存在和位置在这种细胞周期阻滞中起重要作用。对于左芳环对位的这种取代似乎是一个先决条件。然而，抗雌激素活性的构效关系似乎不同，但实验信息过于有限，无法确定可能的构效关系。总之，我们的研究表明，一些与万络相关的合成顺式芪可能具有化学预防特性，可有效干扰乳腺肿瘤细胞的细胞周期分布。
