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

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 Fe3+. 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.