Biological Activity
Non-nucleoside DNA methyltransferase inhibitor that blocks the enzyme active site. Inhibits DNA methylation in human cancer cell lines in vitro without detectable toxicity. Demethylates and reactivates epigenetically silenced tumor suppressor genes.
Description
RG-108 (48208-26-0) is a non-nucleoside DNA methyltransferase inhibitor. IC50=115 nM1 Inhibits DNA methylation in human tumor cell lines without toxicity2. RG-108 enhances the reversion of neural progenitor cells to the pluripotent state.3
Uses
RG108 has been used:
- in reprogramming and increasing cell plasticity of primary multipotent mesenchymal stromal cells (MMSC)
- as an inhibitor of DNA methyltransferase (DNMTi) in human retinal pigment epithelial ARPE-19 cells
- as a DNA methyltransferase inhibitor in C33A2 cells to test its effect on papillomavirus late gene expression (HPV16)
Uses
DNA methylation regulates gene expression in normal and malignant cells. RG-108 is a non-nucleoside DNA methyltransferase inhibitor (IC50 = 115 nM in vitro). It significantly reduces the methylation of genomic DNA in cells at 10 μM without detectable toxicity, distinguishing it from nucleoside-based inhibitors like 5-azacytidine. Further, RG-108 inhibits DNA methyltransferase activity by blocking the enzyme active site. Through these actions, RG-108 demethylates and reactivates epigenetically silenced tumor suppressor genes.
Definition
ChEBI: (2S)-2-(1,3-dioxo-2-isoindolyl)-3-(1H-indol-3-yl)propanoic acid is an indolyl carboxylic acid.
General Description
RG108, a non-nucleoside analog is also called [2-(1,3-dioxoisoindolin-2-yl)-3-(1H-indol-3-yl) propanoic acid.
Biochem/physiol Actions
RG108 is a DNA methyltransferase (DMNT) inhibitor. It reactivates tumor suppressor gene expression (p16, SFRP1, secreted frizzled related protein-1, and TIMP-3) in tumor cells by DNA demethylation. RG108 also inhibits human tumor cell line (HCT116, NALM-6) proliferation and increased doubling time in culture.
Synthesis
The general procedure for the synthesis of milnacipran from L-tryptophan and 2,5-dioxopyrrolidin-1-methyl phthalate is as follows: the reaction of RG108 with L-tryptophan was carried out in a mixed solvent of water/acetonitrile under alkaline conditions (Na2CO3). After completion of the reaction, the reaction mixture was acidified with 2N HCl and subsequently extracted with ethyl acetate. The extract was evaporated to remove the solvent and the target product was obtained in 100% yield. The resulting pure yellow powder was analyzed by mass spectrometry (ESI) and 1H- and 13C-NMR for structural confirmation.
References
1) Brueckner et al. (2005), Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferase; Cancer Res., 65 6305
2) Stresemann et al. (2006), Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines; Cancer Res., 66 2794
3) Szablowska-Gadomska et al. (2012), Treatment with small molecules is an important milestone towards the induction of pluripotency in neural stem cells derived from human cord blood; Acta Neurobiol. Exp., 72 337
