Cancer specific N-alkylaminoferrocene-based prodrugs

n -烷基氨基二茂（NAAF）前药在活性氧（ROS）浓度升高的情况下被激活，形成高毒性物质。这些情况是癌细胞的特征，而正常细胞具有较低的稳态ROS水平。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。在先前dfg资助的先前项目的框架中，我们通过将这些前药重定向到溶酶体来增强其功效，溶酶体中的ROS浓度高于癌细胞的细胞质。此外，我们证实了前药对癌细胞系和原代细胞的功效不依赖于p53。最好的naaf前药显示出体内抗癌活性，其剂量比基于体外数据预测的剂量高100 - 20倍。我们观察到，至少其中一个可能的原因是血液中前体药物的细胞非特异性氧化导致它们失活。在这个项目中，我们将通过对前体药物的二茂铁核心进行氧化还原调整来解决这个问题，而不影响通过切割B-C键引发的理想的癌症特异性ros触发的激活反应。接下来，我们将通过使用比之前使用的（过氧化氢）更具活性的触发器（过氧亚硝酸盐）进一步提高前药的功效，使其降至nMolar范围。将对前药进行设计/优化，以实现原位生成的ONOO-a与芳基硼酸触发器的有效反应，从而避免ONOO-泄漏到可能导致潜在副作用的环境中。在体外细胞培养实验和体内NK/淋巴瘤小鼠模型中药物在肿瘤中的分布和积累以及前药的抗肿瘤功效的研究中，将对所得前药的特性进行评估。

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.