Anticancer (hexacarbonyldicobalt)propargyl aryl ethers: synthesis, antiproliferative activity, apoptosis induction, and effect on cellular oxidative stress.
Anticancer (hexacarbonyldicobalt)propargyl aryl ethers: synthesis, antiproliferative activity, apoptosis induction, and effect on cellular oxidative stress.
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DOI：
10.1016/j.jinorgbio.2012.10.014
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发表时间：
2013-02
影响因子：
3.9
通讯作者：
Sydonie D Schimler;D. Hall;Stefan L. Debbert
中科院分区：
文献类型：
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作者：
Sydonie D Schimler;D. Hall;Stefan L. Debbert
虽然越来越多的（六羰基二钴）炔已被发现具有抗肿瘤细胞系的抗增殖活性，在这种生物活性的有机金属部分的作用还没有得到很好的理解。为了更好地了解钴在这些化合物的药物化学中的作用，合成了已知有机钴抗癌化合物的几种简化类似物，并评估了对MDA-MB-231人乳腺癌细胞的抗增殖活性。在72小时结晶紫染色试验中，这些化合物（主要是（六羰基二钴）炔丙基芳基醚）在40μM时对该细胞系的生长抑制率为45-93%。活性最高的类似物是有机钴硝基芳香醚3a，IC 50为3.3±0.9μM。对同一细胞系的流式细胞术测定表明，3a强烈诱导细胞凋亡，将细胞周期阻滞在S期，增加细胞氧化应激水平，并诱导线粒体膜的通透性。虽然3a的不含钴的前体也引起线粒体膜通透性的增加，但它不产生氧化应激水平的增加，也不具有凋亡诱导或抗增殖作用。细胞中氧化应激的诱导可能是化合物3a对该细胞系的一些抗增殖活性的原因。
While an increasing number of (hexacarbonyldicobalt)alkynes have been found to possess antiproliferative activity against a number of cancer cell lines, the role of the organometallic moiety in this bioactivity is not well understood. To gain a better understanding of cobalt's role in the medicinal chemistry of these compounds, several simplified analogs of a known organocobalt anticancer compound were synthesized and assessed for antiproliferative activity against MDA-MB-231 human breast cancer cells. These compounds, mostly (hexacarbonyldicobalt)propargyl aryl ethers, caused 45–93% growth inhibition of that cell line at 40μM in a 72h crystal violet staining assay. The most active analog was the organocobalt nitroaromatic ether 3a, with an IC50of 3.3±0.9μM. Flow cytometric assays on the same cell line demonstrated that 3a strongly induces apoptosis, arrests the cell cycle at the S phase, increases cellular oxidative stress levels, and induces permeability of the mitochondrial membrane. While the non-cobalt-containing precursor to 3a also caused an increase in mitochondrial membrane permeability, it did not produce an increase in oxidative stress levels, nor did it have apoptosis-inducing or antiproliferative effects. The induction of oxidative stress in the cell may be responsible for some of the antiproliferative activity of compound 3a against this cell line.