Cancer specific N-alkylaminoferrocene-based prodrugs

癌症特异性 N-烷基氨基二茂铁前药

• 批准号: 260329470
• 负责人: Professor Dr. Andriy Mokhir
• 金额: --
• 依托单位: Professur für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/260329470?language=en
• 关键词: Cancer; specific; alkylaminoferrocene; based; prodrugs

N-alkylaminoferrocene-based (NAAF) prodrugs are activated in the presence of elevated concentrations of reactive oxygen species (ROS) with formation of highly toxic species. These conditions are characteristic for cancer cells, whereas normal cells have low homeostatic ROS levels. Therefore, NAAF-prodrugs kill cancer cells preferably over normal ones as we have established in both in vitro and in vivo experiments. In the framework of the previously DFG-funded previous project we enhanced the efficacy of these prodrugs by their redirection to lysosomes, where the ROS concentration is higher than that in cytoplasm of cancer cells. Moreover, we confirmed that the efficacy of the prodrugs towards both cancer cell lines and primary cells is not p53-dependent. The best NAAF-prodrugs exhibit in vivo anticancer activity at >20-fold higher doses than those predicted based on in vitro data. We observed that at least one of the possible reasons for that is a cell-unspecific oxidation of prodrugs in blood leading to their deactivation. In this project we will approach this problem by redox-tuning of the ferrocene core of the prodrugs without affecting the desirable, cancer specific ROS-triggered activation reaction initiated by cleavage of the B-C bond. Next, we will further enhance the efficacy of the prodrugs down to the nMolar range by making use of a substantially more reactive trigger (peroxynitrite) than that previously used (hydrogen peroxide). The prodrug will be designed / optimized to achieve the efficient reaction of in situ generated ONOO-a with the arylboronic acid trigger thereby avoiding the leakage of ONOO- to the environment that could cause potential side effects. Properties of the resulting prodrug will be evaluated both in vitro in experiments with cell cultures and in vivo in studies of drug distribution and accumulation in tumors and antitumor efficacy of the prodrug in an NK/lymphoma mouse model.

基于 N-烷基氨基二茂铁 (NAAF) 的前药在活性氧 (ROS) 浓度升高的情况下被激活，并形成剧毒物质。这些条件是癌细胞的特征，而正常细胞的稳态 ROS 水平较低。因此，正如我们在体外和体内实验中所证实的那样，NAAF-前药比正常细胞更能杀死癌细胞。在之前 DFG 资助的项目框架中，我们通过将这些前药重定向到溶酶体来增强它们的功效，溶酶体中的 ROS 浓度高于癌细胞细胞质中的浓度。此外，我们证实前药对癌细胞系和原代细胞的功效不依赖于 p53。最好的 NAAF 前药在体内抗癌活性的剂量比基于体外数据预测的剂量高 20 倍以上。我们观察到，至少其中一个可能的原因是血液中前药的细胞非特异性氧化导致其失活。在这个项目中，我们将通过对前药的二茂铁核心进行氧化还原调节来解决这个问题，而不影响由 B-C 键裂解引发的理想的癌症特异性 ROS 触发的激活反应。接下来，我们将通过使用比以前使用的触发剂（过氧化氢）反应性更高的触发剂（过氧亚硝酸盐），进一步将前药的功效提高到 nMolar 范围。该前药将经过设计/优化，以实现原位生成的 ONOO-a 与芳基硼酸触发剂的有效反应，从而避免 ONOO- 泄漏到环境中，从而导致潜在的副作用。所得前药的特性将在体外细胞培养实验和体内药物在肿瘤中的分布和积累研究以及前药在 NK/淋巴瘤小鼠模型中的抗肿瘤功效研究中进行评估。