Friedrich-Alexander University Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry Chair II, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
Friedrich-Alexander University Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry Chair II, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany.
J Inorg Biochem. 2022 Aug;233:111859. doi: 10.1016/j.jinorgbio.2022.111859. Epub 2022 May 13.
Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.
含有二茂铁和苯酚残基的杂化药物，其π系统彼此不共轭，具有先前报道的强大抗癌活性。在这些药物实际应用之前，仍有几个重要的悬而未决的问题。首先，它们的作用模式尚未完全阐明。其次，尚不清楚这些药物是否表现出癌细胞特异性。第三，由于存在酚部分，这些药物在体内应用时可能会由于酚羟基的存在而被氧化失活并通过 II 相代谢消除。在本文中，我们报告了三种氨基二茂铁-苯酚杂化物前药的合成，其中酚羟基被掩蔽为硼酸频哪醇酯。我们证实，在这个小系列中，最好的前药 p5 在人卵巢癌细胞 A2780 和 Burkitt 淋巴瘤 BL-2 细胞中被激活，但在代表性的正常 SBLF9 细胞中保持不活跃。由于 p5 不含游离的酚羟基，因此它不会在体内作为酚类物质代谢。我们证实，氨基二茂铁-苯酚前药 p5 的抗癌活性机制依赖于细胞中活性氧的生成。
