Al-Kazaale Nora, Tran Phuong T, Haidari Farhad, Solum Eirik Johansson, Liekens Sandra, Vervaeke Peter, Sylte Ingebrigt, Cheng Jing-Jy, Vik Anders, Hansen Trond Vidar
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway; Faculty of Health Sciences, Nord University, 7801 Namsos, Norway.
Steroids. 2018 Aug;136:47-55. doi: 10.1016/j.steroids.2018.05.002. Epub 2018 May 18.
The endogenous steroid 2-methoxyestradiol (1) has attracted a great interest as a lead compound towards the development of new anti-cancer drugs. Herein, the synthesis, molecular modeling, anti-proliferative and anti-angiogenic effects of ten 2-ethyl and four 2-methoxy analogs of estradiol are reported. The ethyl group was introduced to the steroid A-ring using a novel Friedel-Crafts alkylation protocol. Several analogs displayed potent anti-proliferative activity with IC-values in the submicromolar range towards the CEM human leukemia cancer cell line. As such, all of these compounds proved to be more active than the lead compound 2-methoxyestradiol (1) in these cells. The six most cytostatic analogs were also tested as anti-angiogenic agents using an in vitro tube formation assay. The IC-values were determined to be in the range of 0.1 μM ± 0.03 and 1.1 μM ± 0.2. These six compounds were also modest inhibitors against tubulin polymerization with the most potent inhibitor was 14b (IC = 2.1 ± 0.1 μM). Binding studies using N,N'-ethylene-bis(iodoacetamide) revealed that neither14a or 14b binds to the colchicine binding site in the tubulin protein, in contrast to 2-methoxyestradiol (1). These observations were supported by molecular modeling studies. Results from a MDA-MB-231 cell cycle assay showed that both 10e and 14b gave accumulation in the G2/M phase resulting in induction of apoptosis. The results presented herein shows that the novel analogs reported exhibit their anticancer effects via several modes of action.
内源性甾体2-甲氧基雌二醇（1）作为开发新型抗癌药物的先导化合物引起了广泛关注。本文报道了十种雌二醇的2-乙基类似物和四种2-甲氧基类似物的合成、分子建模、抗增殖和抗血管生成作用。使用新型傅克烷基化方案将乙基引入甾体A环。几种类似物表现出强大的抗增殖活性，对CEM人白血病癌细胞系的IC值在亚微摩尔范围内。因此，所有这些化合物在这些细胞中都比先导化合物2-甲氧基雌二醇（1）更具活性。还使用体外管形成试验对六种最具细胞抑制作用的类似物作为抗血管生成剂进行了测试。测定的IC值在0.1μM±0.03和1.1μM±0.2范围内。这六种化合物也是微管蛋白聚合的适度抑制剂，最有效的抑制剂是14b（IC = 2.1±0.1μM）。使用N，N'-亚乙基双（碘乙酰胺）的结合研究表明，与2-甲氧基雌二醇（1）不同，14a和14b都不与微管蛋白中的秋水仙碱结合位点结合。这些观察结果得到了分子建模研究的支持。MDA-MB-231细胞周期试验的结果表明，10e和1 + 4b都在G2 / M期积累，导致细胞凋亡的诱导。本文给出的结果表明，所报道的新型类似物通过多种作用方式发挥其抗癌作用。
