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

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• 作者：Jinxu Qi ; Yi Gou ; Yao Zhang ; Kun Yang ; Shifang Chen ; Li Liu ; Xiaoyang Wu ; Tao Wang ; Wei Zhang ; Feng Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7497-7511
• 全文大小：892K
• 年卷期：0
• ISSN：1520-4804

文摘

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.