Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity
Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity
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DOI：
10.1007/s00775-004-0541-4
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发表时间：
2004-06-01
影响因子：
3
通讯作者：
Bierbach, U
中科院分区：
文献类型：
--
作者：
Ackley, MC;Barry, CG;Bierbach, U
本文报道了由典型化合物[PtCl（en）（ACRAMTU）]（NO_3）（2）{“PT-ACRAMTU”; en=乙烷-1，2-二胺，ACRAMTU=1-[2-（吖啶-9-基氨基）乙基]-1，3-二甲基硫脲，质子化形式}衍生的铂-吖啶基硫脲偶联物的合成、细胞毒性和与核苷的结合。为了在这类化合物中建立结构-活性关系，对硫脲非离去基团进行了系统的改变，该基团将嵌入剂与铂联系起来。生成了三种新的ACRAMTU衍生物，一种是二烷基化的，一种是三烷基化的，一种是四烷基化的，其中烷基化程度表示连接到SCN 2框架上的烷基的数量。随后的三烷基化和四烷基化衍生物与活化的[PtCl 2（en）]反应产生相应的铂缀合物。二烷基化硫脲产生不稳定的络合物，其未包括在研究中。测定了PT-ACRAMTU·MeOH的晶体结构。在固态下，正方形平面铂配位球的一个轴向位置部分地被庞大的硫脲基团屏蔽，为化合物的动力学惰性提供了强有力的理由。使用克隆形成存活测定法在卵巢癌（A2780、A2780/CP）、肺癌（NCI-H460）和结肠癌（RKO）细胞系中评估原型、两种新缀合物和顺铂的细胞毒性。含有三烷基硫脲基团的衍生物显示出与顺铂相似或上级的活性，IC 50值在低微摩尔浓度范围内。用四烷基化（体积最大）硫脲修饰的复合物活性显著降低，可能是由于与核碱基氮的结合速率大大降低（H-1 NMR光谱），但在克服A2780/CP中对顺铂的交叉耐药性方面最有效。这些代理商的作用机制的报告的结构修改的可能后果进行了讨论。
The synthesis, cytotoxicity, and nucleoside binding of some platinum-acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)(2) {"PT-ACRAMTU"; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form} are reported. To establish structure-activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU.MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (H-1 NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.