School of Chemistry, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK.
School of Biosciences, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK.
Chembiochem. 2020 Sep 1;21(17):2487-2494. doi: 10.1002/cbic.202000124. Epub 2020 May 19.
Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1-(S,R ), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1-(S,R ), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic. On the other hand, methylated derivatives of 1-(S,R ) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1-(S,R ) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity.
四种新型双取代二茂铁衍生物，分别含有羟烷基或甲氧基烷基以及胸腺嘧啶基或甲基胸腺嘧啶基，已通过一系列光谱和分析技术进行了合成和表征。它们被包含在一个结构-活性关系（SAR）研究中，以研究骨肉瘤（骨癌）细胞系中的抗癌活性，并与一种已知的先导化合物 1-（S,R ）进行了比较，1-（S,R ）是一种核苷类似物，对癌细胞具有高度毒性。使用 MTT 测定的生物学研究表明，1-（S,R ）的一个区域异构体，与先导化合物的区别仅在于两个茂环上取代而不是一个，其细胞毒性低 20 多倍。另一方面，1-（S,R ）的甲基化衍生物表现出与先导化合物相当的细胞毒性。总的来说，这些研究表明，1-（S,R ）的作用机制不能通过醇磷酸化进行，其几何形状和大小而不是任何特定的功能基团，是解释其高抗癌活性的关键因素。
