Exploring pyrimidine-substituted curcumin analogues: design, synthesis and effects on EGFR signaling.
Exploring pyrimidine-substituted curcumin analogues: design, synthesis and effects on EGFR signaling.
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DOI：
10.1016/j.bmc.2013.06.053
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发表时间：
2013-09
影响因子：
3.5
通讯作者：
Peiju Qiu;Lingling Xu;Lei Gao;Meng Zhang;Shixi Wang;Sheng Tong;Yue Sun;Lijuan Zhang;Tao Jiang
中科院分区：
文献类型：
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作者：
Peiju Qiu;Lingling Xu;Lei Gao;Meng Zhang;Shixi Wang;Sheng Tong;Yue Sun;Lijuan Zhang;Tao Jiang
表皮生长因子受体（EGFR）是抗癌治疗的有效分子靶点。姜黄素通过抑制EGFR的基因表达在体外抑制癌细胞生长，并在各种动物模型中减少肿瘤生长。为了克服姜黄素作为治疗剂的不稳定性和不溶性，我们设计并合成了六种新颖的嘧啶取代的姜黄素类似物，其具有或不具有最初存在于姜黄素中的羟基。细胞活性测试表明，含羟基的类似物的IC 50比不含羟基的类似物的IC 50低3至8倍。Western blot分析表明，含羟基的类似物抑制EGFR的表达和酪氨酸磷酸化。进一步的蛋白质分析表明，类似物具有抗细胞增殖，促细胞凋亡和细胞周期阻滞特性与抑制EGFR表达。这些结果表明姜黄素及其类似物中的羟基对所观察到的生物活性至关重要。
Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.