Synthesis of Xanthohumol Analogues and Discovery of Potent Thioredoxin Reductase Inhibitor as Potential Anticancer Agent

• Published in: Journal of medicinal chemistry 2015-02, Vol.58 (4), p.1795-1805
• Main Authors: Zhang, Baoxin, Duan, Dongzhu, Ge, Chunpo, Yao, Juan, Liu, Yaping, Li, Xinming, Fang, Jianguo
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; HeLa Cells; Hep G2 Cells; HL-60 Cells; Humans; Molecular Structure; Propiophenones - chemical synthesis; Propiophenones - chemistry; Propiophenones - pharmacology; Structure-Activity Relationship; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Thioredoxin-Disulfide Reductase - metabolism; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5016507

The selenoprotein thioredoxin reductases (TrxRs) are attractive targets for anticancer drugs development. Xanthohumol (Xn), a naturally occurring polyphenol chalcone from hops, has received increasing attention because of its multiple pharmacological activities. We synthesized Xn and its 43 analogues and discovered that compound 13n displayed the highest cytotoxicity toward HeLa cells (IC50 = 1.4 μM). Structure–activity relationship study indicates that the prenyl group is not necessary for cytotoxicity, and introducing electron-withdrawing group, especially on the meta-position, is favored. In addition, methylation of the phenoxyl groups generally improves the potency. Mechanistic study revealed that 13n selectively inhibits TrxR and induces reactive oxygen species and apoptosis in HeLa cells. Cells overexpressing TrxR are resistant to 13n insult, while knockdown of TrxR sensitizes cells to 13n treatment, highlighting the physiological significance of targeting TrxR by 13n. The clarification of the structural determinants for the potency would guide the design of novel potent molecules for future development.