Novel half-sandwich iridium(III) imino-pyridyl complexes showing remarkable in vitro anticancer activity,Dalton Transactions

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Novel half-sandwich iridium(III) imino-pyridyl complexes showing remarkable in vitro anticancer activity
Dalton Transactions ( IF 3.5 ) Pub Date : 2017-10-17 00:00:00 , DOI: 10.1039/c7dt03265j
JuanJuan Li _{1,

2,

3,

4,

5} , Lihua Guo _{1,

2,

3,

4,

5} , Zhenzhen Tian _{1,

2,

3,

4,

5} , Meng Tian _{1,

2,

3,

4,

5} , Shumiao Zhang _{1,

2,

3,

4,

5} , Ke Xu _{1,

2,

3,

4,

5} , Yuchuan Qian _{1,

2,

3,

4,

5} , Zhe Liu _{1,

2,

3,

4,

5}

Affiliation

Seven novel half-sandwich Ir^III cyclopentadienyl complexes, [(η⁵-Cp^x)Ir(N^N)Cl]PF₆, have been prepared and characterized, where Cp^x is Cp* or the biphenyl derivative Cp^xbiph (C₅Me₄C₆H₄C₆H₅), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp^xbiph complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NAD⁺via hydride transfer. Cp^xbiph complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G₂/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity.

中文翻译：

新型半三明治铱（III）亚氨基-吡啶基复合物显示出显着的体外抗癌活性

七新颖半夹心铱^III环戊二烯基络合物，[（η ⁵ -Cp ^X）IR（N ^ N）CL] PF ₆，已经制备和表征，其中Cp ^X为Cp *或联苯衍生物的Cp ^xbiph（C ₅ Me ₄ C ₆ H ₄ C ₆ H ₅）和N 2 N-螯合配体是亚氨基吡啶基席夫碱。配合物2A，2B和3A的X射线晶体结构已经确定。令人兴奋的是，除Cp *复合物1A对HeLa细胞外，大多数复合物均对A549和HeLa癌细胞显示有效的抗增殖活性。cp ^xbiph复合物2B具有最高的效力，分别比临床使用的顺铂药物对A549和HeLa细胞的活性高19倍和6倍。这些配合物进行水解，并计算了动力学数据。已经通过与核碱基9-乙基鸟嘌呤和9-甲基腺嘌呤相互作用，质粒DNA裂解以及与ctDNA相互作用研究了DNA结合。与DNA的相互作用似乎不是主要的作用机理。蛋白结合（牛血清白蛋白，BSA）已通过紫外可见，荧光和同步光谱研究建立。评价了复合物2B在GSH存在下的稳定性。该络合物通过氢化物转移将辅酶NADH催化转化为NAD ⁺。cp ^xbiph复合物2B和4B在S和G ₂ / M期诱导细胞凋亡并将细胞周期阻滞向A549癌细胞，并显着增加活性氧，这似乎有助于显着的抗癌活性。

更新日期：2017-11-15

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