RG108性質(zhì)、用途與生產(chǎn)工藝
RG108是一種DNA甲基轉(zhuǎn)移酶抑制劑，IC50為115 nM，不會(huì)引起共價(jià)酶的誘捕。
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)是一種DNA methyltransferase抑制劑，無細(xì)胞試驗(yàn)中IC50為115 nM，不會(huì)引起共價(jià)酶的誘捕。
| Target | Value |
DNA methyltransferase
(Cell-free assay)
|
115 nM
|
RG108有效阻斷體外人細(xì)胞系中DNA甲基轉(zhuǎn)移酶，并且不會(huì)引起共價(jià)酶俘獲。細(xì)胞用低微摩爾濃度的RG108培育，導(dǎo)致基因組DNA顯著脫甲基化，而沒有可檢測的毒性。有趣的是，RG108引起腫瘤抑制基因脫甲基和再活化，但是它不影響著絲?；蛐蛄械募谆?。在另一個(gè)研究中，進(jìn)行生物素化RG108綴合物的合成和體外分析以評(píng)估與DNA甲基轉(zhuǎn)移酶的相互作用。最近的研究表明，與天然SMs相比，RG108能夠顯著降低SM衍生的iPS細(xì)胞中DNA活性。
生產(chǎn)方法
以L-色氨酸和2,5-二氧代吡咯烷-1-甲基鄰苯二甲酸酯為原料合成米爾納西普蘭的一般步驟如下：在堿性條件下（Na2CO3），于水/乙腈混合溶劑中，RG108與L-色氨酸反應(yīng)。反應(yīng)完成后，用2N HCl酸化反應(yīng)混合物，隨后用乙酸乙酯萃取。萃取液經(jīng)蒸發(fā)去除溶劑，以100%的產(chǎn)率獲得目標(biāo)產(chǎn)物。所得純黃色粉末通過質(zhì)譜（ESI）及1H-和13C-NMR分析進(jìn)行結(jié)構(gòu)確認(rèn)。
參考文獻(xiàn)：
[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
RG108
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