Design and synthesis of water-soluble grifolin prodrugs for DNA methyltransferase 1 (DNMT1) down-regulation

  • RSC Adv. 2021 Dec 3;11(61):38907-38914. doi: 10.1039/d1ra06648j.
Liguo Wang  1 ,  Yue Wu  1 ,  Zhenzhen Li  2  3  4  5 ,  Tianlong Lan  1 ,  Xu Zhao  2  3  4  5 ,  Wenxing Lv  1 ,  Feng Shi  2  3  4  5 ,  Xiangjian Luo  2  3  4  5 ,  Yu Rao  1 ,  Ya Cao  2  3  4  5
Affiliations
  • 1. Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University Beijing 100084 China [email protected].
  • 2. Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Central South University Changsha 410078 China [email protected].
  • 3. Cancer Research Institute, School of Basic Medicine, Central South University Changsha 410078 China.
  • 4. Molecular Imaging Research Center of Central South University Changsha China.
  • 5. National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer Changsha 410078 China [email protected] [email protected].
PMID: 35493211 DOI: 10.1039/d1ra06648j
Abstract

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 in vivo. PEG5-Grifolin might be a promising demethylation agent for DNMT1 associated diseases and benefit much against various types of DNMT1 associated Cancer.

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