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.
The Front Cover shows the bioconjugation of an antiproliferative prochelator to serum albumin via formation of a disulfide bond with a reduced cysteine on the protein. The abundance of albumin in blood is represented by the red background featuring red blood cells. The disulfide‐masked prochelators of this class have antiproliferative activities at submicromolar levels in a panel of cancer cell lines. Cover design by Matthew W. Lluis. More information can be found in the Communication by Elisa Tomat et al..
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