Novel organo-osmium(II) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans,Inorganic Chemistry Frontiers

当前位置： X-MOL 学术 › Inorg. Chem. Front. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Novel organo-osmium(II) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans
Inorganic Chemistry Frontiers ( IF 6.1 ) Pub Date : 2020-10-27 , DOI: 10.1039/c9qi01704f
Enrique Ortega _{1,

2,

3,

4,

5} , Francisco J. Ballester _{1,

2,

3,

4,

5} , Alba Hernández-García _{1,

2,

3,

4,

5} , Samanta Hernández-García _{2,

4,

6,

7,

8} , M. Alejandra Guerrero-Rubio _{2,

4,

6,

7,

8} , Delia Bautista _{2,

4,

5,

9} , M. Dolores Santana _{1,

2,

3,

4,

5} , Fernando Gandía-Herrero _{2,

4,

6,

7,

8} , José Ruiz _{1,

2,

3,

4,

5}

Affiliation

This work reports the synthesis and characterization of some novel osmium(II) complexes with potential as anticancer drugs tested in vitro and in vivo. The complexes have a structure [(η⁶-p-cym)Os(C^N)(X)]^0/+, where the C^N ligand is deprotonated 2-phenylpyridine (ppy) or 4-(2-pyridin)benzaldehyde (ppy-CHO) and X is chloride, pyridine (py) or the pyridine derivative 4-NMe₂-py. The in vitro cytotoxic studies showed that complexes [(η⁶-p-cym)Os(C^N)(4-NMe₂-py)]⁺ (C^N = ppy 2a and ppy-CHO 5a) exerted effective antiproliferative activity towards both cisplatin-sensitive ovarian cancer cells (A2780) and cisplatin-resistant cells (A2780cis). The mechanism underlying the antiproliferative effects in vitro was studied showing a reduction of proteosynthesis up to 58% and an increase of apoptosis modulated by caspase-3. Model animal Caenorhabditis elegans was used to estimate the effects of 2a and 5a and the in-house 4-NMe₂-py Ru(II) analogue 5b in vivo. Compounds 2a, 5a and 5b were able to reduce tumor growth up 32.2%, 19% and 30%, respectively in the tumoral strain JK1466 and presented low toxicity in both tumoral and wild-type strains. The mechanistic study using reporter gene expression showed that 2a, 5a and 5b were able to maintain the reactive oxygen species (ROS) levels in the animals by increased expression of the mitochondrial superoxide dismutase 3 (SOD-3), an indication that they were able to regulate oxidative stress genes specifically. Interestingly the three complexes showed a similar mechanism of action, suggesting that the identity of the metal ion does not matter and the effect is more related to the whole structure of the complex. Worthy of note, cisplatin treatment produced elevated ROS levels in the animals and induced the expression of glutathione transferase 4 (GST-4) suggesting different mechanisms of action for the two complexes. Altogether the results showed that osmium(II) complexes can be potential candidates in the search for novel chemotherapeutic drugs.

中文翻译：

对人卵巢癌细胞有活性的新型有机organo（II）蛋白合成抑制剂可降低秀丽隐杆线虫的性腺肿瘤生长

这项工作报告了一些新颖的（II）配合物的合成和表征，这些配合物具有作为抗癌药的潜力，已在体内和体外进行了测试。所述配合物具有结构[（η ⁶ - p -cym）OS（C ^ N）（X）] ^{0 / +}，其中C ^ N配体去质子化2-苯基吡啶（PPY）或4-（2-吡啶）苯甲醛（ppy-CHO），X是氯，吡啶（py）或吡啶衍生物4-NMe ₂ -py。在体外细胞毒性研究表明，配合物[（η ⁶ - p -cym）OS（C ^ N）（4-NME ₂ -py）] ⁺（C ^ N = PPY 2A和PPY-CHO 5A）对顺铂敏感的卵巢癌细胞（A2780）和对顺铂耐药的细胞（A2780cis）均具有有效的抗增殖活性。研究了体外抗增殖作用的机制，显示蛋白质合成减少多达58％，caspase-3调节的细胞凋亡增加。使用模型动物秀丽隐杆线虫（Caenorhabditis elegans）来评估2a和5a以及室内4-NMe ₂ -py Ru（II）类似物5b的 作用。化合物2a，5a和5b在肿瘤菌株JK1466中，它们能够分别降低肿瘤生长32.2％，19％和30％，并且在肿瘤和野生型菌株中均显示出低毒性。使用报告基因表达的机理研究表明2a，5a和5b能够通过增加线粒体超氧化物歧化酶3（SOD-3）的表达来维持动物体内的活性氧（ROS）水平，这表明它们能够特异性调节氧化应激基因。有趣的是，这三种配合物显示出相似的作用机理，这表明金属离子的身份无关紧要，其作用与配合物的整个结构更相关。值得注意的是，顺铂处理在动物体内产生了升高的ROS水平，并诱导了谷胱甘肽转移酶4（GST-4）的表达，表明这两种复合物的作用机理不同。总体而言，结果表明，（（II）配合物可能是寻找新型化疗药物的潜在候选者。

更新日期：2020-11-12

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11