Qi Jinxu, Gou Yi, Zhang Yao, Yang Kun, Chen Shifang, Liu Li, Wu Xiaoyang, Wang Tao, Zhang Wei, Yang Feng
School of Pharmacy, Nantong University , Nantong, Jiangsu 226019, China.
Department of Biology, Southern University of Science and Technology , Shenzhen, Guangdong 518055, China.
J Med Chem. 2016 Aug 25;59(16):7497-511. doi: 10.1021/acs.jmedchem.6b00509. Epub 2016 Aug 8.
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.
为了提高三价铁（Fe）抗癌剂的选择性、递送效率和活性，我们基于人血清白蛋白（HSA）载体IIA亚结构域的氮供体残基设计了前药。我们合成了六种源自2-羟基-1-萘甲醛硫代半卡巴腙的铁（III）化合物（7-12）。HSA复合物结构表明，铁化合物与人血清白蛋白IIA亚结构域中的疏水腔结合。HSA的Lys199和His242取代了铁化合物的两个氯原子，与Fe（3+）配位。体内数据表明，化合物12和HSA-12复合物可抑制肝肿瘤生长，且HSA-12复合物比单独的化合物12具有更强的靶向能力和治疗效果。此外，我们的结果表明，化合物12和HSA-12复合物可能通过多种机制诱导Bel-7402细胞死亡。
