C3′/C4′-Stereochemical Effects of Digitoxigenin α-L-/α-D-Glycoside in Cancer Cytotoxicity
C3′/C4′-Stereochemical Effects of Digitoxigenin α-L-/α-D-Glycoside in Cancer Cytotoxicity
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DOI：
10.1002/cmdc.201200465
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
O'Doherty, George A.
中科院分区：
文献类型：
--
作者：
Hinds, John W.;McKenna, Sean B.;O'Doherty, George A.
洋地黄毒素是一种有效的强心剂，几个世纪以来一直用于治疗充血性心力衰竭，最近被认为是在肿瘤学中的潜在应用。[1-3]洋地黄毒素强心作用的作用机制是通过抑制细胞外Na+/K+-ATPase泵导致钙离子内流增加而发生的。[4]与强心作用相比，人们对其抗肿瘤活性的机制知之甚少。[5]已表明细胞死亡是通过细胞凋亡发生的。谢[6-8]领导的几项研究表明，在癌细胞中，心脏糖苷结合的Na+/K+-ATPase复合体通过Src-酪氨酸激酶和1，4，5-三磷酸肌醇(IP3)发出信号，这几个下游事件最终导致细胞凋亡。这种信号通路被认为是通过Na+/K+-ATPase泵的特定亚型发生的，这种泵与癌症有关，而不是与心脏组织相关。这些对癌细胞具有强大细胞毒性的有希望的发现启发了许多结构-活性关系(SAR)研究，主要目的是了解碳水化合物在心脏糖苷的细胞毒性中所起的作用。这些研究包括糖苷键的直接比较，[9，10]糖链长度的研究，[10，11]洋地黄毒素单糖的立体化学调查，[12]以及对C5‘-烷基立体效应的研究。[13]这些基于碳水化合物的SAR研究导致了新的糖基序的发现，显著提高了对一系列癌细胞的细胞毒性。[12]到目前为止，我们发现洋地黄毒素α-L-鼠李糖-单糖1在最广泛的细胞系中是最活跃的类似物，α-L-酰胺4的结果次之。C2‘/C3’-二脱氧鼠李糖类似物(α-L-amiceto 4)在抗癌活性方面的惊人相似性促使我们探索其他可以进一步增强细胞毒性的脱氧模式。
Digitoxin, a potent cardiotonic agent that has been used continuously over centuries for the treatment of congestive heart failure, has more recently been recognized for its potential application in oncology.[1–3] The mechanism of action for digitoxin cardiotonic effect occurs via an increase of Ca2+ influx as a result of inhibition of the extracellular Na+/K+-ATPase pump.[4] In contrast to the cardiotonic effects, less detail is known for the mechanism of antitumor activity.[5] It has been shown that cell death occurs via apoptosis. Several studies led by Xie [6–8] have suggested that, in cancer cells, a cardiac glycoside-bound Na+/K+-ATPase complex signals via Src-tyrosine kinase and 1, 4, 5-triphosphoinositol (IP3), several downstream events that ultimately lead to apoptosis. This signaling pathway is believed to occur through specific isoforms of the Na+/K+-ATPase pump, which are associated with cancer and not heart tissue.These promising findings of potent cytotoxicity against cancer cells inspired many structural–activity relationship (SAR) studies, primarily aimed at understanding the role that the carbohydrate plays in the cytotoxicity of the cardiac glycosides. These studies include direct comparison of glycosidic linkage,[9, 10] the study of sugar-chain length,[10, 11] the stereochemical survey of digitoxin monosaccharides,[12] and the study of C5’-alkyl steric effect.[13] These carbohydrate-based SAR studies have led to the discovery of new sugar motifs that significantly improved the cytotoxicity across a range of cancer cell lines.[12] To date, we have found that digitoxin α-L-rhamno-monosaccharide 1 to be the most active analogue across the widest range of cell lines, with α-L-amiceto 4 having the next best results. This surprising similarity in anticancer activity of the C2’/C3’-dideoxy-rhamno-analogue (α-L-amiceto 4) motivated us to explore other deoxygenation patterns that could further enhance the cytotoxicity.