Developing Anticancer Ferric Prodrugs Based on the N-Donor Residues of Human Serum Albumin Carrier IIA Subdomain

Abstract

To improve the selectivity, delivery, and activity of ferric (Fe) anticancer agents, we design prodrugs based on N-donor residues of the human serum albumin (HSA) carrier IIA subdomain. We synthesized six Fe(III) compounds derived from 2-hydroxy-1-naphthaldehyde thiosemicarbazone (7-12). HSA complex structure revealed that Fe compound binds to the hydrophobic cavity in the HSA IIA subdomain. Lys199 and His242 of HSA replace the two Cl atoms of Fe compound, coordinating with Fe(3+). In vivo data revealed that compound 12 and HSA-12 complex inhibit the growth of the liver tumor and that the HSA-12 complex has stronger targeting ability and therapeutic efficacy than compound 12 alone. In addition, our results have shown that compound 12 and HSA-12 complex induce Bel-7402 cell death possible by several mechanisms.

Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery

“…This compound achieved better selectivity and ability to inhibit tumor growth compared with the free copper compound alone in vivo . Ferric anticancer agents were also reported to bind to albumin and inhibit tumor growth in vivo 175 . Three anti-tumor drugs, namely, 5-fluorouracil, a copper (II)-based anti-tumor agent and a gene agent, were co-loaded in albumin by hydrophobic interaction or covalent conjugation 176 .…”

Effects of Terminal Substitution and Iron Coordination on Antiproliferative Activity of l‐Proline‐salicylaldehyde–Thiosemicarbazone Hybrids

“…The Fe–O, Fe–N, Fe–S, and Fe–Cl bond lengths in 3 and 4′ are markedly longer than those in a series of iron(III) complexes with 2‐hydroxy‐1‐naphthaldehyde‐thiosemicarbazones reported recently . This is probably due to the different coordination numbers in the two types of compounds and reduced ligand–ligand repulsions in five‐coordinate iron(III) complexes with 2‐hydroxy‐1‐naphthaldehyde‐thiosemicarbazones …”

“…Its derivatives H 2 L 3 and H 2 L 4 are most probably more lipophilic due to the presence of the phenyl and naphthyl groups, what is advantageous for the easier passage through the biological membranes resulting in the increased cytotoxicity. The drug delivery and activity of the iron complexes might be improved by attaching them to a prodrug carrier as recently published for a series of related iron complexes . All those iron complexes possess one tridendate Schiff base ligand (modified just at the terminal N atom), one iron center, and two chloride ligands (as leaving groups) …”

“…The drug delivery and activity of the iron complexes might be improved by attaching them to a prodrug carrier as recently published for a series of related iron complexes . All those iron complexes possess one tridendate Schiff base ligand (modified just at the terminal N atom), one iron center, and two chloride ligands (as leaving groups) …”

“…Complexes of TSCs with essential transition‐metal ions do not always exhibit better in vitro cytotoxicity than metal‐free TSCs alone , , , . According to the previous studies, only few iron–TSC complexes showed an improved cytotoxic effect upon coordination to iron , . Although they can activate various pathways leading ultimately to cell apoptosis, their mechanism of inhibition of cell proliferation is still unknown.…”