NQO1-Selective Activated Prodrug of Triptolide: Synthesis and Antihepatocellular Carcinoma Activity Evaluation
NQO1-Selective Activated Prodrug of Triptolide: Synthesis and Antihepatocellular Carcinoma Activity Evaluation
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DOI：
10.1021/acsmedchemlett.8b00404
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发表时间：
2018-12-01
影响因子：
4.2
通讯作者：
Peng, Zhihong
中科院分区：
文献类型：
--
作者：
Liu, Meilin;Song, Wei;Peng, Zhihong
肝细胞癌（HCC）是肝硬化患者死亡的主要原因。由于其对常规化疗药物的反应较差，其生存预后最差。 NAD(P)-H:醌氧化还原酶 1 (NQO1) 由于其在 HCC 中过度表达而成为一个有吸引力的抗癌靶点。尽管雷公藤内酯醇（TP）具有有效的抗肿瘤活性，但由于其普遍的毒性和狭窄的治疗窗，其临床应用受到很大限制。在此，我们开发了一种 NQO1 选择性激活的 TP 类似物，命名为 CX-23，其在体外表现出对正常肝细胞的 HepG2 增殖抑制作用。体内研究表明CX-23不仅可以阻止肝细胞癌的进展，还可以转移肝肾毒性。这些发现表明，NQO1 可以作为释放抗肿瘤试剂的靶向递送系统，而 CX-23 可能是开发靶向抗肝细胞癌药物的有前景的先导药物。
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Due to its poor response to conventional chemotherapy drugs, the prognosis for its survival is the worst. NAD(P)-H:quinone oxidoreductase 1 (NQO1) is an attractive anticancer target due to its overexpression in HCC. Although triptolide (TP) possesses potent antitumor activity, its clinical practice is greatly limited due to its general toxicities and narrow therapeutic window. Herein, we develop an NQO1-selective activated TP analog, named CX-23, which exhibited antiproliferation of HepG2 over normal hepatocytes in vitro. In vivo study shows that CX-23 can not only prevent the hepatocellular carcinoma progression but also migrate the liver and kidney toxicity. These findings indicate that NQO1 may serve as a targeted delivery system to release an antitumor reagent and that CX-23 may be a promising lead for developing targeted antihepatocellular carcinoma drugs.