Metal complexes targeting tumour metastasis and vascularisation on a cellular and molecular level

每年死于癌症的800万人中，超过90%死于癌症转移。虽然原发性肿瘤的治疗已经取得了很大的进展，但临床对转移的控制仅限于筛选潜在的靶器官和肿瘤标志物。市场上没有专门的抗转移药物。该项目旨在开发专门针对在转移过程的各个阶段发挥关键作用的蛋白质的药物，例如癌细胞入侵邻近组织和发展中的微肿瘤的血管化。结构方面，重点是晚期过渡金属配合物与螯合和碳配体从固有的生物活性天然产物衍生。这些配合物通过修饰其有机配体和利用其中心金属碎片的氧化还原特性、配位模式和几何形状，提供了许多方法来微调其对靶蛋白的亲和力和影响。在第二个资助期，我们将改进先前被确定为原转移蛋白抑制剂的复杂基序，例如抑制神经酰胺酶的茂金属-鞘复合物。此外，我们还将设计新的配合物，从具有弱抗转移副作用的现有癌症药物中提取配体，以增强后者并克服母体药物的药理缺陷。我们将探索这一策略，以开发血管生成和转移性缺氧诱导因子抑制剂，以及抗代谢物氟达拉滨的复杂衍生物，氟达拉滨是癌症治疗的临床支柱。新的复合物将在体外和体内对植入受精卵的绒毛膜尿囊膜和斑马鱼的微肿瘤进行疗效评估。对实际肿瘤患者的干细胞样循环上皮癌细胞进行测试，将允许为未来的转移指定最合适的药物。

Over 90% of the eight million cancer dead every year died of metastases. While the therapy of primary tumours has made great progress, the clinical control of metastasis is limited to a mere screening of potential target organs and tumour markers. There is no dedicated anti-metastatic drug on the market. This project aims to develop drugs that specifically address proteins which play crucial roles in the various stages of the metastasis process, e.g. the invasion of neighbouring tissues by cancer cells and the vascularisation of developing microtumours. Structurewise, the focus is on complexes of late transition metals with chelate and carbene ligands derived from inherently bioactive natural products. These complexes offer many ways of fine-tuning their affinity for and impact on target proteins by modifying their organic ligands and by exploiting the redox properties, coordination modes and geometries of their central metal fragments.In the second funding period we will refine complex motifs that had previously been identified as inhibitors of prometastatic proteins, e.g. metallocenyl–sphingoid complexes which inhibit ceramidase. In addition, we will also devise new complexes bearing ligands derived from established cancer drugs with weakly antimetastatic side effects in order to potentiate the latter and overcome the pharmacological shortcomings of the parent drug. We will explore this strategy for the development of inhibitors of the angiogenic and prometastatic hypoxia-inducible factor, and for complex derivatives of the antimetabolite fludarabine, a clinical mainstay of cancer therapy.The efficacy of new complexes will be evaluated in vitro and also in vivo on developing microtumours implanted in the chorioallantoic membrane of fertilised chicken eggs and in zebrafish. Tests on stem-cell-like circulating epithelial cancer cells of actual tumour patients will allow to earmark the most appropriate drug for a future metastasis.