Department of Chemistry and Biochemistry, The University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721-0041, USA.
ChemMedChem. 2021 Sep 16;16(18):2764-2768. doi: 10.1002/cmdc.202100278. Epub 2021 Jun 10.
The central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2 : 1 ligand-to-metal complexes. Native mass spectrometry experiments show that the prochelators form stable disulfide conjugates with bovine serum albumin, thus affording novel bioconjugate prochelator systems. Antiproliferative activities at sub-micromolar levels are recorded in a panel of breast, ovarian and colorectal cancer cells, along with significantly lower activity in normal fibroblasts.
铁在肿瘤进展和转移中的核心作用促使人们开发用于癌症化疗的铁结合方法。基于二硫键的前螯合剂在细胞摄取后被还原激活，释放负责铁螯合的硫醇螯合剂。在此，三甲基硫代半卡巴腙部分和咪唑-2-硫酮杂环被纳入该前螯合剂设计中。相应的三齿螯合剂与铁的结合导致在 2：1 的配体与金属配合物中稳定低自旋的三价铁中心。天然质谱实验表明，前螯合剂与牛血清白蛋白形成稳定的二硫键缀合物，从而提供了新的生物缀合前螯合物系统。在一系列乳腺癌、卵巢癌和结直肠癌细胞中，亚微米级水平的抗增殖活性被记录下来，而在正常成纤维细胞中的活性显著降低。
