泽布拉林作用机制- Medchemexpress- MCE中国

Product Data?SheetZebularineCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-134203690-10-6C?H??N?O?228.2DNA Methyltransferase; AutophagyEpigenetics; AutophagyPowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMSO : ≥ 100 mg/mL (438.21 mM)H2O : 50 mg/mL (219.11 mM; Need ultrasonic)* \Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM4.3821 mL0.8764 mL0.4382 mL21.9106 mL4.3821 mL2.1911 mL43.8212 mL8.7642 mL4.3821 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；?旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。体内实验请根据您的实验动物和给药?式选择适当的溶解?案。以下溶解?案都请先按照 In Vitro ?式配制澄清的储备液，再依次添加助溶剂： 为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的?作液，建议您现?现配，当天使?； 以下溶剂前显?的百分?是指该溶剂在您配制终溶液中的体积占?；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的?式助溶1. 请依序添加每种溶剂：?10% DMSO ?? 40% PEG300 ?? 5% Tween-80 ?? 45% salineSolubility: ≥ 2.5 mg/mL (10.96 mM); Clear solution此?案可获得 ≥ 2.5 mg/mL (10.96 mM，饱和度未知) 的澄清溶液。 以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加? 50 μL Tween-80，混合均匀；然后继续加? 450 μL ?理盐?定容? 1 mL。2. 请依序添加每种溶剂：?10% DMSO ?? 90% (20% SBE-β-CD in saline)Solubility: ≥ 2.5 mg/mL (10.96 mM); Clear solutionPage 1 of 2 www.MedChemExpress.cn

此?案可获得 ≥ 2.5 mg/mL (10.96 mM，饱和度未知) 的澄清溶液。

以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD ?理盐??溶液中，混合均匀。

3. 请依序添加每种溶剂：?10% DMSO ?? 90% corn oilSolubility: ≥ 2.5 mg/mL (10.96 mM); Clear solution

此?案可获得 ≥ 2.5 mg/mL (10.96 mM，饱和度未知) 的澄清溶液，此?案不适?于实验周期在半个?以上的实验。 以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL ??油中，混合均匀。

BIOLOGICAL ACTIVITY

?物活性IC?? & Target

Zebularine (NSC309132; 4-Deoxyuridine)是DNA甲基转移酶抑制剂；也可抑制胞苷脱氨酶，Ki值为0.95 μM。DNMT1?

体外研究

DNMT3a/3L?

Cytidine deaminase0.95 μM (Ki)

Autophagy?

Zebularine exerts its demethylation activity by stabilizing the binding of DNMTs to DNA, hindering the methylation and decreasing the dissociation, thereby trapping the enzyme and preventing turnover even at other sites. zebularine enhances tumor cell chemo- and radiosensitivity and has antimitogenic and angiostatic activities[1]. Zebularine inhibits DNA methylation and reactivates a gene previously silenced by methylation. 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 demethylated its promoter region in T24 bladder carcinoma cells[2]. Zebularine treatment inhibits cell growth in a dose and time dependent manner with an IC50 of -100 μM and 150 μM in MDA-MB-231 and MCF-7 cells, respectively, on 96 h exposure. At high doses zebularine induced changes in apoptotic proteins in a cell line specific manner manifested by alteration in caspase-3, Bax, Bcl2 and PARP cleavage[3]. Zebularine is also a potent competitive inhibitor of the enzyme CR deaminase. The Ki for zebularine is 0.95μM[4].

体内研究

Zebularine is only slightly cytotoxic to tumor-bearing mice. 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[2]. Zebularine also enhances the survival time of mice with L1210 leukemia treated with 5-AZA-CdR. About 27% of the mice treated with this drug combination has a survival time longer than the mice treated with only 5-AZA-CdR[4].

PROTOCOL

Cell Assay [2]

For methylation analysis, 10T1/2 cells and T24 cells are treated with the various concentrations of zebularine. For 10T1/2 cells, the medium is changed 24 hours after the initial drug treatment, whereas for T24 cells, the medium is changed 24 hours or 48 hours after the initial drug treatment. DNA and RNA are harvested from 10T1/2 cells 72 hours after initial drug treatment and from T24 cells 96 hours after initial drug treatment. The methylation status of the indicated DNA regions is measured in two separate and independent experiments, both of which are done in duplicate[2].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal

Administration [2]

EJ6 cells (5 × 105/injection) suspended in PBS are inoculated subcutaneously into the right and left flanks (along the midaxillary lines) of 4- to 6-week-old male BALB/c nu/nu mice. Mice (n=30) are randomLy divided into six groups (intraperitoneal control, oral control, intraperitoneal zebularine at 500 mg/kg, oral zebularine at 500 mg/kg, intraperitoneal zebularine at 1000 mg/kg, and oral zebularine at 1000 mg/kg). Each group consisted of five mice (at least six tumors per group; one or two mice per group are randomLy killed at earlier time points to establish a time

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course of expression). After 2–3 weeks and after macroscopic tumors (50–200 mm3) had formed, zebularine or control treatments are initiated. Zebularine, at doses of 500 mg/kg or 1000 mg/kg, is administered daily by intraperitoneal injection or oral gavage in a solution of 0.45% saline over a period of 18 days[2].MCE has not independently confirmed the accuracy of these methods. They are for reference only.

客户使?本产品发表的科研?献

????Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2961-2966.????BMC Genomics.?2019 Oct 15;20(1):736.????Patent. US20180263995A1.

See more customer validations on www.MedChemExpress.cnREFERENCES

[1].?Champion C, et al. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One. 2010 Aug 24;5(8):e12388.[2].?Cheng JC, et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst. 2003 Mar 5;95(5):399-409.

[3].?Billam M, et al. Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. Breast Cancer Res Treat. 2010 Apr;120(3):581-92.

[4].?Lemaire M, et al. Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2'-deoxycytidine. Cancer Chemother Pharmacol. 2009 Feb;63(3):411-6.

McePdfHeightCaution: Product has not been fully validated for medical applications. For research use only.

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