用于下调DNA甲基转移酶1（DNMT1）的水溶性鹰爪豆素前药的设计与合成。
Design and synthesis of water-soluble grifolin prodrugs for DNA methyltransferase 1 (DNMT1) down-regulation.
作者信息
Wang Liguo, Wu Yue, Li Zhenzhen, Lan Tianlong, Zhao Xu, Lv Wenxing, Shi Feng, Luo Xiangjian, Rao Yu, Cao Ya
机构信息
Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University Beijing 100084 China
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Central South University Changsha 410078 China
出版信息
RSC Adv. 2021 Dec 3;11(61):38907-38914. doi: 10.1039/d1ra06648j. eCollection 2021 Nov 29.
DNA methylation and gene silencing play indispensable roles in the epigenetic landscape and gene expression. DNA methyltransferase 1 (DNMT1), a member of the DNMT family, which catalyzes the addition of methyl groups on DNA has been identified to have a close relationship with tumorigenesis. But DNMT1 inhibitors are rare except for the highly toxic nucleoside derivates. Grifolin is a unique natural product which down-regulates DNMT1 and has low toxicity. However, the poor solubility and stability of grifolin limit its application. Herein, we synthesized PEG5-Grifolin as a water-miscible prodrug of grifolin. The half-life of PEG5-Grifolin at 25 °C was considerably extended, revealing excellent stability. Meanwhile, PEG5-Grifolin suppressed tumor growth of by downregulating DNMT1 and reactivating the expression of several tumor suppressor genes . PEG5-Grifolin might be a promising demethylation agent for DNMT1 associated diseases and benefit much against various types of DNMT1 associated cancer.
DNA甲基化和基因沉默在表观遗传格局和基因表达中发挥着不可或缺的作用。DNA甲基转移酶1（DNMT1）是DNMT家族的成员，它催化DNA上甲基基团的添加，已被确定与肿瘤发生密切相关。但是除了毒性很强的核苷衍生物外，DNMT1抑制剂很少见。落叶松脂醇是一种独特的天然产物，它能下调DNMT1且毒性较低。然而，落叶松脂醇的溶解性和稳定性较差，限制了其应用。在此，我们合成了PEG5-落叶松脂醇作为落叶松脂醇的一种可与水混溶的前药。PEG5-落叶松脂醇在25℃下的半衰期显著延长，显示出优异的稳定性。同时，PEG5-落叶松脂醇通过下调DNMT1和重新激活几个肿瘤抑制基因的表达来抑制肿瘤生长。PEG5-落叶松脂醇可能是一种用于治疗与DNMT1相关疾病的有前途的去甲基化剂，对各种类型的与DNMT1相关的癌症可能有很大益处。
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