Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma
Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma
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口服吲哚取代的二吡啶并[2,3-d]嘧啶衍生物通过抑制 AKT 和 ERK1/2 对肝细胞癌发挥抗肿瘤活性
DOI：
10.1016/j.bbrc.2018.09.120
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发表时间：
2018
影响因子：
3.1
通讯作者：
Zhu Songlei
中科院分区：
文献类型：
--
作者：
Gao Xiaoge;Cen Lanqi;Li Fangyuan;Wen Ren;Yan Hongru;Yao Hong;Zhu Songlei
开发有效、安全的抗癌药物是治疗肝细胞癌的迫切要求。在本研究中，我们以3-氰乙酰基吲哚1、多种芳香醛2和2，6-二氨基嘧啶-4(~3H)-酮3为原料，通过多组分反应连接吡啶并[2，3-d]嘧啶和吲哚基团，合成了一系列新型吲哚取代二氢吡啶并[2，3-d]嘧啶类化合物。随后，我们通过CCK-8法对其在人肝癌细胞株HepG2中的细胞毒作用进行了筛选，并选择了IC50剂量最低的化合物4P来研究其抗肝癌活性。有趣的是，4P在体外通过靶向AKT和ERK1/2信号通路显著诱导HepG2细胞周期停滞和凋亡。为了改善化合物4P的溶解性，我们将该化合物托管在(2-羟丙基)-β-环糊精(HBc)取代的吡喃葡萄糖环上，HBc是FDA批准的助溶剂，通过超声和加热。最后，在皮下移植模型中，我们证明了口服HBc-Hosted4有效地抑制了肿瘤的生长，延长了荷瘤小鼠的生存时间。这些结果表明，将吡啶并[2，3-d]嘧啶与吲哚基团连接起来的多组分反应是合成抗癌化合物的一种高效、经济的方法，口服HBc-Hosted 4p是一种有效、安全的治疗肝癌的药物，其临床应用潜力值得进一步研究。
Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles1, various aromatic aldehyde2,and 2,6-diaminopyrimidin-4(3H)-one3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound4pthat showed the lowest dosage of IC50 to study the antitumor activities to HCC. Interestingly,4psignificantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and ERK1/2 signaling pathwaysin vitro. To improve the solubility of compound4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)-β-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted4peffectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted4pis an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies.