Organometallic Osmium(II) Arene Anticancer Complexes Containing Picolinate Derivatives

Chlorido osmium(II) arene [(η6-biphenyl)OsII(X-pico)Cl] complexes containing X = Br (1), OH (2), and Me (3) as ortho, or X = Cl (4), CO2H (5), and Me (6) as para substituents on the picolinate (pico) ring have been synthesized and characterized. The X-ray crystal structures of 1 and 6 show typical “piano-stool” geometry with intermolecular π-π stacking of the biphenyl outer rings of 6. At 288 K the hydrolysis rates follow the order 2 ≫ 6 > 4 > 3 > 5 ≫ 1 with half-lives ranging from minutes to 4.4 h illustrating the influence of both electronic and steric effects of the substituents. The pKa values of the aqua adducts 3A, 4A, 5A, and 6A were all in the range of 6.3−6.6. The para-substituted pico complexes 4−6 readily formed adducts with both 9-ethyl guanine (9EtG) and 9-ethyl adenine (9EtA), but these were less favored for the ortho-substituted complexes 1 and 3 showing little reaction with 9EtG and 9EtA, respectively. Density-functional theory calculations confirmed the observed preferences for nucleobase binding for complex 1. In cytotoxicity assays with A2780, cisplatin-resistant A2780cis human ovarian, A549 human lung, and HCT116 colon cancer cells, only complexes 4 (p-Cl) and 6 (p-Me) exhibited significant activity (IC50 values < 25 μM). Both of these complexes were as active as cisplatin in A2780 (ovarian) and HCT116 (colon) cell lines, and even overcome cisplatin resistance in the A2780cis (ovarian) cell line. The inactivity of 5 is attributed to the negative charge on its para carboxylate substituent. These data illustrate how the chemical reactivity and cancer cell cytotoxicity of osmium arene complexes can be controlled and “fine-tuned” by the use of steric and electronic effects of substituents on a chelating ligand to give osmium(II) arene complexes which are as active as cisplatin but have a different mechanism of action.

本研究合成并表征了一系列氯代锇(II)芳烃配合物，其通式为[(η⁶-联苯)Os(II)(X-吡啶甲酸根)Cl]，其中吡啶甲酸根（picolinate，缩写pico）环上的取代基X为邻位时分别为溴（Br，配合物1）、羟基（OH，配合物2）和甲基（Me，配合物3）；为对位时分别为氯（Cl，配合物4）、羧基（CO₂H，配合物5）和甲基（Me，配合物6）。配合物1和6的X射线晶体结构显示其具有典型的“钢琴凳”构型，其中配合物6的联苯外环存在分子间π-π堆积作用。在288 K条件下，各配合物的水解速率顺序为2 ≫ 6 > 4 > 3 > 5 ≫ 1，半衰期跨度为数分钟至4.4小时，这体现了取代基的电子效应与位阻效应的共同影响。水加合物3A、4A、5A和6A的pKa值均处于6.3~6.6的区间内。对位取代的pico配合物4~6可与9-乙基鸟嘌呤（9EtG）和9-乙基腺嘌呤（9EtA）顺利形成加合物，而邻位取代的配合物1和3则较难发生此类反应，分别仅与9EtG和9EtA发生微弱反应。密度泛函理论计算验证了配合物1对核碱基结合的选择性偏好。在针对人卵巢癌A2780、顺铂耐药型人卵巢癌A2780cis、人肺癌A549以及结直肠癌HCT116细胞的细胞毒性测定中，仅配合物4（对位氯取代）和6（对位甲基取代）表现出显著的细胞毒性（半数抑制浓度（IC50）<25 μM）。在A2780（卵巢癌）与HCT116（结直肠癌）细胞系中，这两种配合物的活性均与顺铂相当，且在A2780cis（顺铂耐药卵巢癌）细胞系中甚至可逆转顺铂耐药性。配合物5无活性的原因在于其对位羧基取代基带有负电荷。上述实验数据表明，通过调控螯合配体上取代基的位阻效应与电子效应，可对锇芳烃配合物的化学反应活性与癌细胞毒性进行精准调控与优化，从而获得活性与顺铂相当但作用机制迥异的锇(II)芳烃配合物。