RG108

RG108是一种DNA甲基转移酶抑制剂，IC50为115 nM，不会引起共价酶的诱捕。 RG108 effectively blocks DNA methyltransferases in vitro and does not cause covalent enzyme trapping in human cell lines. Incubation of cells with low micromolar concentrations of RG108 results in significant demethylation of genomic DNA without any detectable toxicity. Intriguingly, RG108 causes demethylation and reactivation of tumor suppressor genes, but it does not affect the methylation of centromeric satellite sequences. In another study, the synthesis and in vitro analysis of a biotinylated RG108 conjugate is investigated to evaluate the interactions with DNA methyltransferase enzymes. In a recent study, it is shown RG108 can significantly reduce the DNA methyltransferases activity in SM derived iPS cells as compared to the native SMs. RG108 (N-Phthalyl-L-tryptophan)是一种DNA methyltransferase抑制剂，无细胞试验中IC50为115 nM，不会引起共价酶的诱捕。

Target	Value
DNA methyltransferase (Cell-free assay)	115 nM

RG108有效阻断体外人细胞系中DNA甲基转移酶，并且不会引起共价酶俘获。细胞用低微摩尔浓度的RG108培育，导致基因组DNA显著脱甲基化，而没有可检测的毒性。有趣的是，RG108引起肿瘤抑制基因脱甲基和再活化，但是它不影响着丝粒基因序列的甲基化。在另一个研究中，进行生物素化RG108缀合物的合成和体外分析以评估与DNA甲基转移酶的相互作用。最近的研究表明，与天然SMs相比，RG108能够显著降低SM衍生的iPS细胞中DNA活性。

以L-色氨酸和2,5-二氧代吡咯烷-1-甲基邻苯二甲酸酯为原料合成米尔纳西普兰的一般步骤如下：在碱性条件下（Na2CO3），于水/乙腈混合溶剂中，RG108与L-色氨酸反应。反应完成后，用2N HCl酸化反应混合物，随后用乙酸乙酯萃取。萃取液经蒸发去除溶剂，以100%的产率获得目标产物。所得纯黄色粉末通过质谱（ESI）及1H-和13C-NMR分析进行结构确认。

参考文献：

[1] Patent: EP1574499, 2005, A1. Location in patent: Page/Page column 14

[2] Organic Letters, 2012, vol. 14, # 1, p. 90 - 93

[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 421 - 434

[4] Patent: WO2007/7054, 2007, A1. Location in patent: Page/Page column 48; 53