Friedrich-Alexander University Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry Chair II, Nikolaus-Fiebiger-Str. 10, 91058, Erlangen, Germany.
Institute of Experimental Botany AS CR, Prague, Czech Republic.
Angew Chem Int Ed Engl. 2021 May 10;60(20):11158-11162. doi: 10.1002/anie.202100054. Epub 2021 Apr 8.
The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.
在癌细胞的内质网（ER）中，蛋白质的折叠和输出以及未折叠蛋白质的水解失去平衡，导致所谓的 ER 应激。包括临床上已批准的蛋白酶体抑制剂硼替佐米和卡非佐米在内的，进一步增强这种效应的药物被用作抗癌药物。然而，这些药物会影响正常细胞，而正常细胞强烈依赖 ER 功能，导致活性氧（ROS）的积累。为了解决这个问题，我们开发了仅在存在高 ROS 水平时在癌细胞中被激活的 ER 靶向前药。这些化合物是胆酸与基于 N-烷基氨基二茂铁的前药的轭合物。我们证实了它们在癌细胞 ER 中的积累、它们的抗癌功效和癌细胞特异性。这些前药诱导 ER 应激，减弱线粒体膜电位，并产生线粒体 ROS，导致通过坏死导致细胞死亡。我们还证明了新的前药在 Nemeth-Kellner 淋巴瘤（NK/Ly）小鼠模型中在体内被激活。
