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

在细胞和分子水平上靶向肿瘤转移和血管化的金属配合物

• 批准号: 278267910
• 负责人: Professor Dr. Rainer Schobert
• 金额: --
• 依托单位: Arbeitsgruppe Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/278267910?language=en
• 关键词: Metal; complexes; targeting; tumour; metastasis

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.

每年死于癌症的800万人中有90%以上死于转移。虽然原发性肿瘤的治疗已经取得了很大进展，但转移的临床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，例如癌细胞对邻近组织的入侵和发展中微肿瘤的血管化。在结构上，重点是后过渡金属与螯合物和卡宾配体的络合物，这些配体来自具有内在生物活性的天然产物。这些配合物提供了许多方法微调其亲和力和影响的目标蛋白通过修改其有机配体，并通过利用其中心金属fragment.In第二个资助期的氧化还原特性，配位模式和几何形状，我们将完善复杂的图案，以前已被确定为抑制剂的促转移蛋白，如cefenyl-sphingoid复合物，抑制神经酰胺酶。此外，我们还将设计新的配合物轴承配体来自已建立的抗癌药物具有弱抗转移的副作用，以加强后者，克服了母体药物的药理学缺点。我们将探索这种策略的发展抑制剂的血管生成和促转移缺氧诱导因子，并为复杂的衍生物的抗代谢物氟达拉滨，临床中流砥柱的癌症therapy.The疗效的新的复合物将在体外和体内发育中的microtumor植入受精鸡蛋和斑马鱼的绒毛尿囊膜。对实际肿瘤患者的干细胞样循环上皮癌细胞的测试将允许为未来的转移指定最合适的药物。

项目成果

Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors.

• DOI: 10.1039/c9dt02438g
• 发表时间: 2019-11
• 期刊: Dalton transactions
• 影响因子: 4
• 作者: Tobias Rehm;M. Rothemund;T. Dietel;R. Kempe;R. Schobert

Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(ii) complexes.

• DOI: 10.1039/d0dt01664k
• 发表时间: 2020-06
• 期刊: Dalton transactions
• 影响因子: 4
• 作者: M. Rothemund;Sofia I. Bär;Tobias Rehm;H. Kostrhunová;V. Brabec;R. Schobert

A new 4-(pyridinyl)-4H-benzo[g]chromene-5,10-dione ruthenium(II) complex inducing senescence in 518A2 melanoma cells

一种新的 4-(吡啶基)-4H-苯并[g]色烯-5,10-二酮钌(II)复合物诱导 518A2 黑色素瘤细胞衰老

• DOI: 10.1007/s00775-019-01677-y
• 发表时间: 2019
• 期刊: JBIC Journal of Biological Inorganic Chemistry
• 作者: Gold M;Mujahid Y;Ahmed K;Biersack B;Schobert R.
• 通讯作者: Schobert R.

Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N-Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group.

• DOI: 10.1021/acs.jmedchem.5b00896
• 发表时间: 2015-07
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Julienne K. Muenzner;Tobias Rehm;B. Biersack;A. Casini;I. A. D. de Graaf;Pawida Worawutputtapong;A. Noor;R. Kempe;V. Brabec;J. Kašpárková;R. Schobert

Antiparasitic activities of bimetallic N‐heterocyclic carbene gold(I) complexes with ferrocene ligands: relevance of chlorido and phosphino ligands

双金属Nâ杂环卡宾金(I)与二茂铁配体配合物的抗寄生虫活性：氯代和膦基配体的相关性

• DOI: 10.1002/aoc.6952
• 发表时间: 2022
• 期刊: Applied Organometallic Chemistry
• 影响因子: 3.9
• 作者: Al Nasr I.S;Weise M;Koko W.S;Khan T.A;Schobert R;Biersack B.
• 通讯作者: Biersack B.