Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
J Med Chem. 2010 Nov 25;53(22):8012-20. doi: 10.1021/jm100758j. Epub 2010 Oct 28.
A stereoselective synthesis of closo carborane analogues of tamoxifen was developed where the products represent a new approach to developing metabolically robust SERMs. The A-ring found in the backbone of tamoxifen was replaced with an ortho carborane cluster; the product was determined to be the desired Z isomer, which showed superior chemical stability to tamoxifen both in solution and in the solid state. By use of microwave heating, it was possible to convert some of the Z carborane tamoxifen analogue to the corresponding E isomer. Cell growth assays using both isomers and a carborane that is known to target the ER were conducted using estrogen receptor (ER) positive and ER negative human breast cancer cells with and without the presence of estradiol (E2). The Z carborane isomer was able to inhibit cell proliferation better than tamoxifen in an E2 free environment, while the E isomer inhibited cell growth better than tamoxifen when E2 was present.
开发了一种对映选择性合成他莫昔芬类似物的 closo 碳硼烷，这些产物代表了开发代谢稳定的 SERM 的新方法。他莫昔芬骨架中的 A 环被邻位碳硼烷簇取代；该产物被确定为所需的 Z 异构体，它在溶液中和固态中均显示出比他莫昔芬更好的化学稳定性。通过使用微波加热，有可能将一些 Z 碳硼烷他莫昔芬类似物转化为相应的 E 异构体。使用雌激素受体 (ER) 阳性和 ER 阴性人乳腺癌细胞，在有或没有雌二醇 (E2) 的情况下，使用两种异构体和已知靶向 ER 的碳硼烷进行细胞生长测定。在没有 E2 的环境中，Z 碳硼烷异构体比他莫昔芬更能抑制细胞增殖，而当存在 E2 时，E 异构体比他莫昔芬更能抑制细胞生长。
