Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Département de Chimie-Biologie, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada G9A 5H7.
Steroids. 2012 Apr;77(5):403-12. doi: 10.1016/j.steroids.2011.12.021. Epub 2011 Dec 29.
L-para-Tyrosine was linked to ortho-hydroxyaniline, meta-hydroxyaniline and para-hydroxyaniline giving three distinct tyrosinamide molecules. The new extended amino acid derivatives were constructed to imitate, in part, the estradiol (E(2), the natural female sex hormone) nucleus. The resulting tyrosinamides were then linked to chlorambucil either directly, or via a 5 and 10 carbon atoms spacer chain. This was done in an attempt to target cancerous cells expressing the estrogen receptor alpha (ERα) and to obtain a more specific chemotherapeutic agent. The tyrosinamide-chlorambucil molecules were designed and synthesized in good yields, according to two different approaches. The novel compounds were evaluated for their anticancer efficacy in hormone-dependent and hormone-independent (ER+; MCF-7 and ER-; MDA-MB-231) breast cancer cell lines. Interestingly, the meta-hydroxyphenyl-tyrosinamide-chlorambucil derivatives were more active than the ortho- and para- analogs. The molecules bearing a 5 carbon atoms spacer were selected for additional biological study using a panel of female cancerous cells; breast (ZR-75-1, MDA-MB-436, MDA-MB-468), ovarian (OVCAR-3, A2780) and uterine (Ishikawa, HEC-1A). It was discovered that for breast cancer cells, the new compounds were up to 4.2 times more active than chlorambucil itself.
L-对羟苯丙氨酸与邻羟苯胺、间羟苯胺和对羟苯胺相连，形成了三种独特的酪氨酸酰胺分子。这些新的扩展氨基酸衍生物被构建为部分模拟雌二醇（E2，天然女性性激素）的核。然后，将得到的酪氨酸酰胺直接或通过 5 和 10 个碳原子的间隔链与氯苯丁酸相连。这是为了尝试靶向表达雌激素受体 alpha（ERα）的癌细胞，并获得更具特异性的化疗药物。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。根据两种不同的方法，设计并以良好的收率合成了酪氨酸酰胺-氯苯丁酸分子。这些新的化合物在依赖激素和非依赖激素（ER+；MCF-7 和 ER-；MDA-MB-231）的乳腺癌细胞系中进行了抗癌功效评估。有趣的是，间羟苯基-酪氨酸酰胺-氯苯丁酸衍生物比邻羟和对羟类似物更具活性。带有 5 个碳原子间隔链的分子被选择用于使用一组女性癌细胞（乳腺癌 ZR-75-1、MDA-MB-436、MDA-MB-468、卵巢癌 OVCAR-3、A2780 和子宫癌 Ishikawa、HEC-1A）进行进一步的生物学研究。结果发现，对于乳腺癌细胞，新化合物的活性比氯苯丁酸本身高 4.2 倍。
