Swarts Jannie C, Vosloo Theunis G, Cronje Sarina J, Du Plessis W C, Van Rensburg Constance E J, Kreft Elke, Van Lier Johan E
Department of Chemistry, University of Free State, Bloemfontein, 9300, South Africa.
Anticancer Res. 2008 Sep-Oct;28(5A):2781-4.
Oxidised ferrocenium compounds often possess antineoplastic activity. In contrast, reduced ferrocene derivatives frequently only show activity if cell components can oxidise them inside cells to the ferrocenium species. Ferrocene compounds having the lowest formal reduction potential are normally expected to be the most cytotoxic. Here we demonstrate this is not always the case. Some of the structure-related and physical properties that enhance ferrocenyl antineoplastic activity have been investigated.
Ferrocene-containing beta-diketones of the type FcCOCH2COR with Fc=ferrocenyl and R=CF3, CCl3, CH3, Ph(=C6H5, phenyl) and Fc, were tested for cytotoxicity against HeLa (human cervix epitheloid), COR L23 (human large cell lung carcinoma) and platinum resistant CoLo320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay.
The mean drug concentration from 3 experiments causing 50% cell growth inhibition, (IC50) values, varied between 4.5 and 85.0 micromol dm(-3'), with the CF3(-) containing beta-diketone being the most active. Drug activity was inversely proportional to the formal reduction potential, Eo', of the ferrocenyl group, and dependent on the R group in the general beta-diketone structure. The CF3 complex was more cytotocic than cisplatin inter alia against platinum-resistant cell lines, and at least eight times more reactive against cancer cell lines than against PHA (phytohaemagglutinin)-stimulated lymphocyte cultures.
A drug activity-structural relationship exists in that ferrocenyl drugs with halogen substituents chains are more cytotoxic. Compounds with higher ferrocenyl group formal reduction potential and stronger acid strength (i.e. smaller pKa value) are more cytotoxic.
氧化二茂铁化合物通常具有抗肿瘤活性。相比之下，还原态二茂铁衍生物通常只有在细胞成分能将其在细胞内氧化为二茂铁鎓物种时才显示活性。通常认为具有最低形式还原电位的二茂铁化合物具有最强的细胞毒性。然而，我们在此证明情况并非总是如此。本文研究了一些与结构相关且能增强二茂铁基抗肿瘤活性的物理性质。
测试了通式为FcCOCH2COR（其中Fc = 二茂铁基，R = CF3、CCl3、CH3、Ph(=C6H5，苯基) 以及Fc）的含二茂铁β - 二酮对HeLa（人宫颈上皮样细胞）、COR L23（人肺大细胞癌）、铂耐药的CoLo320DM（人结肠直肠癌）以及COR L23/CPR癌细胞系的细胞毒性。通过比色法3 - (4,5 - 二甲基噻唑 - 2 - 基) - 二苯基溴化四氮唑（MTT）法测定细胞存活率。
3次实验中导致50%细胞生长抑制的平均药物浓度（IC50值）在4.5至85.0 μmol dm⁻³之间变化，其中含CF3⁻的β - 二酮活性最高。药物活性与二茂铁基的形式还原电位Eo'成反比，并且取决于一般β - 二酮结构中的R基团。CF3配合物尤其对铂耐药细胞系的细胞毒性比顺铂更强，并且对癌细胞系的反应性比对植物血凝素（PHA）刺激的淋巴细胞培养物至少高8倍。
存在一种药物活性 - 结构关系，即具有卤素取代链的二茂铁基药物细胞毒性更强。具有较高二茂铁基形式还原电位和较强酸强度（即较小的pKa值）的化合物细胞毒性更强。
