Synthesis and evaluation of anticancer activity of BOC26P, an ortho-aryl chalcone sodium phosphate as water-soluble prodrugs in vitro and in vivo
Synthesis and evaluation of anticancer activity of BOC26P, an ortho-aryl chalcone sodium phosphate as water-soluble prodrugs in vitro and in vivo
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邻芳基查尔酮磷酸钠 BOC26P 水溶性前药的合成及体内外抗癌活性评价
DOI：
10.1016/j.biopha.2017.10.006
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发表时间：
2017
影响因子：
7.5
通讯作者：
Zhou BH
中科院分区：
文献类型：
--
作者：
Zhu Cuige;Wang Ruimin;Zheng Weichao;Chen Daoyuan;Yue Xin;Qin Wenjing;Sun Haixia;Wang Youqiao;Liu Ziyi;Du Jun;Bu Xianzhang;Zhou Binhua;Wang Ruimin;Cao Yingnan;Li Baojian;Zhou BH
查尔酮作为临床抗癌药物的主要局限性是水不溶和生物利用度低，这一点可以通过以非特异性碱性磷酸酶(ALP)为靶点的经典磷酸前药策略在体内释放母体药物来改善。在本研究中，我们发现查尔酮OC26的磷酸前体药物BOC26P具有良好的水溶性和改善体内血药浓度的作用。或者是邮政总局。与母体药物相比。随着BOC26P在体外和细胞内对微管聚合抑制活性的降低，BOC26P在A549和HLF细胞中的抗增殖活性也减弱。然而，在A549移植瘤模型中，与等摩尔浓度的OC26相比，BOC26P的抗肿瘤作用增强，提示复杂的肿瘤微环境可能是调节BOC26P体内抗肿瘤活性的另一个重要影响因素。综上所述，这些观察结果表明，传统的磷酸盐前药策略将是一种提高查尔酮类化合物的水溶性和抗癌活性的简单而有前景的方法，为抗癌药物的临床开发奠定了基础。
Major limitations of chalcones as clinical anticancer agents are water insolubility and poor bioavailability, which may be improved by a classic phosphate prodrug strategy that targets non-specific alkaline phosphatase (ALP) for releasing the parent drugin vivo. In this study, we found thatBOC26P, a phosphate prodrug of chalconeOC26, exhibits excellent water solubility and improved plasma concentrationin vivoby either i.v. or p.o. compared with the parent drug. In pace with decreased inhibitory activity ofBOC26Pagainst microtubule polymerizationin vitroand in cells, the antiproliferative activity ofBOC26Pis attenuated in A549 and HLF cells. However, the antitumor effect ofBOC26Pincreases in an A549 xenograft model as compared to the equimolar concentration ofOC26, suggesting that complex tumor microenvironment would be another important influence factor to regulate the antitumor activity ofBOC26Pin vivo. In conclusion, these observations showed that the traditional phosphate prodrug strategy would be a promising and easy method to increase water solubility and anticancer activity of chalcones for the clinical developments of anticancer agents.