Zebularine, 2-嘧啶酮-b-核苷

4-Deoxyuridine

A cytidine analogue and inhibitor of DNA methyl transferases (DNMTs) with anti-cancer activity. This stable, hydrophilic compound forms covalent complexes between DNMT and zebularine-substrate DNA. It causes DNA lesions that block replication and cause replication fork collapse, leading to the formation of DNA double-strand breaks. It was also shown that zebularine-induced DNA methylation decrease in the IL-1β promoter region and disrupts molecular mechanisms of neuroinflammation. Moreover, this molecule down-regulates the DNA-methylation profile in the pluripotency genes’ promoters, which leads to improved development of somatic cell nuclear transfer (SCNT) embryos.

Zebularine, a cytidine analog, is a DNA methylation inhibitor that acts by forming a covalent complex with DNA methyltransferases (DNMTs). By stabilizing the binding of DNMTs to DNA, zebularine hinders methylation and decreases dissociation, trapping DNMT and preventing its turnover. Zebularine preferentially targets cancer cells in various human carcinoma cell lines demonstrating IC20 values of 20, 10, 20, and 5 μM for reducing proliferation of TK6, Jurkat, KG-1, and HCT116 cells, respectively. Zebularine exhibits low toxicity in mice even after prolonged administration (0.2 mg/mL drinking water for 113 days in a mouse intestinal cancer model).

Zebularine(NSC309132; 4-Deoxyuridine) is a DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases, also inhibits cytidinedeaminase with Ki of 2 μM. IC50 value:Target: DNA methyltransferasein vitro: Zebularine is shown to form a tight, covalent complex with bacterial methyltransferases. Zebularine is a cytidine analogue containing a 2-(1H)-pyrimidinone ring, originally synthesized as a cytidine deaminase inhibitor. In N. crassa, zebularine inhibits DNA methylation and reactivates a gene previously silenced by methylation. Zebularine is a global inhibitor of DNA methylation, similar to 5-Aza-CR, rather than a selective inhibitor. Zebularine induces the myogenic phenotype in 10T1/2 cells, which is a phenomenon unique to DNA methylation inhibitors. Zebularine reactivates a silenced p16 gene and demethylates its promoter region in T24 bladder carcinoma cells. Zebularine is only slightly cytotoxic to T24 cells. Zebularine is preferentially incorporated into DNA and exhibits greater cell growth inhibition and gene expression in cancer cell lines compared to normal fibroblasts. In addition, zebularine preferentially depletes DNA methyltransferase 1 (DNMT1) and induces expression of cancer-related antigen genes in cancer cells relative to normal fibroblasts. in vivo: Zebularine is only slightly cytotoxic to tumor-bearing mice (average maximal weight change in mice treated with 1000 mg/kg zebularine = 11% [95% CI = 4% to 19%]). Compared with those in control mice, tumor volumes are statistically significantly reduced in mice treated with high-dose zebularine administered by intraperitoneal injection or by oral gavage.