Preparation and Evaluation of Carborane Analogues of Tamoxifen
Preparation and Evaluation of Carborane Analogues of Tamoxifen
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DOI：
10.1021/jm100758j
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发表时间：
2010-11-25
影响因子：
7.3
通讯作者：
Valliant, John F.
中科院分区：
文献类型：
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作者：
Beer, Michael L.;Lemon, Jennifer;Valliant, John F.
开发了立体选择性合成或紧密碳硼烷类似物或他莫昔芬，其中产物代表了开发代谢稳健的SERM的新方法。用邻位碳硼烷簇取代他莫昔芬骨架中的A-环;产物被确定为所需的Z异构体，其在溶液和固体状态下均显示出比他莫昔芬更上级的化学稳定性。通过使用或微波加热，可以将一些Z碳硼烷他莫昔芬类似物转化为相应的E异构体。在存在和不存在雌二醇（E2）的情况下，使用雌激素受体（ER）阳性和ER阴性人乳腺癌细胞进行使用两种异构体和已知靶向ER的碳硼烷的细胞生长测定。Z碳硼烷异构体能够在无E2的环境中比他莫昔芬更好地抑制细胞增殖，而当E2存在时，E异构体比他莫昔芬更好地抑制细胞生长。
A stereoselective synthesis or closo carborane analogues or tamoxifen was developed where the products represent a new approach to developing metabolically robust SERMs. The A-ring round 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 or 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 or 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.