3-Deazauridine
(Synonyms: 4-羟基-1-Β-D-呋喃核糖苷-2(1H)吡啶酮,NSC 126849) 目录号 : GC42260A nucleoside analog with anticancer activity
Cas No.:23205-42-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
3-Deazauridine is a nucleoside analog. [1] It is converted intracellularly to 3-deazauridine triphosphate, which competitively inhibits cytidine triphosphate synthetase thereby inhibiting biosynthesis of the nucleic acid cytidine 5’-triphosphate (CTP). 3-Deazauridine inhibits the growth of L1210 leukemia cells when used at a concentration of 6 µM and dose-dependently reduces mortality in a mouse model of leukemia.[2] It also enhances the incorporation of decitabine into DNA in HL-60 myeloid and MOLT-3 lymphoid leukemia cells when used at a concentration of 20 µM. 3-Deazauridine (100 or 150 mg/kg), when combined with decitabine, reduces mortality in an L1210 leukemia mouse model.[3]
Reference:
[1]. Moriconi, W.J., Slavik, M., and Taylor, S. 3-Deazauridine (NSC 126849): An interesting modulator of biochemical response. Invest New Drugs 4(1), 67-84 (1986).
[2]. Bloch, A., Dutschman, G., Currie, B.L., et al. Preparation and biological activity of various 3-deazapyrimidines and related nucleosides. J. Med. Chem. 16(3), 294-297 (1973).
[3]. Raynal, N.J.-M., Momparler, L.F., Rivard, G.E., et al. 3-Deazauridine enhances the antileukemic action of 5-aza-2'-deoxycytidine and targets drug-resistance due to deficiency in deoxycytidine kinase. Leuk. Res. 35(1), 110-118 (2011).
| Cas No. | 23205-42-7 | SDF | |
| 别名 | 4-羟基-1-Β-D-呋喃核糖苷-2(1H)吡啶酮,NSC 126849 | ||
| 化学名 | 4-hydroxy-1-β-D-ribofuranosyl-2(1H)-pyridinone | ||
| Canonical SMILES | O=C(C=C(O)C=C1)N1[C@H]2[C@H](O)[C@H](O)[C@@H](CO)O2 | ||
| 分子式 | C10H13NO6 | 分子量 | 243.2 |
| 溶解度 | 10mg/mL in DMSO, 16mg/mL in DMF | 储存条件 | Store at -20°C |
| General tips | 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；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.1118 mL | 20.5592 mL | 41.1184 mL |
| 5 mM | 0.8224 mL | 4.1118 mL | 8.2237 mL |
| 10 mM | 0.4112 mL | 2.0559 mL | 4.1118 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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The mechanism of action of 3-Deazauridine in tumor cells sensitive and resistant to arabinosylcytosine
Ann N Y Acad Sci 1975 Aug 8;255:501-21.PMID:171997DOI:10.1111/j.1749-6632.1975.tb29254.x.
Deazauridine inhibited growth of tumor cells in culture and in culture and in vivo; this agent was significantly more effective against L1210/AraC than against the parent sensitive line. Inhibition of growth of tumor cells in culture was prevented by uridine and cytidine and was partially alleviated by deoxycytidine, but not by deoxyuridine or thymidine. DeazaUR inhibited nucleic acid synthesis but not protein synthesis in tumor cells in culture; deoxycytidine alleviated inhibition of nucleic acid synthesis. The labeling of pyrimidine ribonucleotides by 6-14C-orotic acid was inhbited by deazaUR. DeazaUR treatment of tumor cells in culture resulted in increased uptake of cytidine-3H into RNA, whereas uridine-3H uptake into RNA was inhibited. Labelling of DNA by uridine-3H/ and cytidine-H was inhibited by deazaUR. Pools of CMP, CDP, and CTP decreased markedly during deazaUR treatment of L1210 cells in culture and in vivo. These observations in growing cells pointed to deazaUR inhibition of the synthesis of cytidylic acid. Deazauridine 5'-triphosphate was found to be an inhibitor of the synthesis of CTP from UTP catalyzed by enzyme preparations from L1210 cells. This observation is in agreement with those of McPartland et al.19 that deazaUTP inhibited CTP synthetase purified from calf liver. Deazauridine treatment of L1210 cells in culture stimulated the uptake of deoxycytidine-3H into DNA while inhibiting the uptake of 3H-labeled deoxyuridine, thymidine, deoxyadenosine, and deoxyguanosine. Intracellular pools of dCTP were decreased by deazauridine treatment in L1210 cells in culture and in vivo. Deazauridine 5'-diphosphate inhibited the enzymatic reduction of pyrimidine ribonucleoside 5'-diphosphates to the corresponding deoxyribonucleotides. These results are consistent with the view that deazauridine, after its uptake and intracellular phosphorylation, strongly inhibits the formation of CTP. This is considered to be the primary metabolic effect of the analog. A secondary effect appears to be an inhibition of dCTP formation.
3-Deazauridine enhances the antileukemic action of 5-aza-2'-deoxycytidine and targets drug-resistance due to deficiency in deoxycytidine kinase
Leuk Res 2011 Jan;35(1):110-8.PMID:20510451DOI:10.1016/j.leukres.2010.04.014.
New approaches should be sought to treat high-risk acute lymphoblastic leukemia (ALL). Since aberrant DNA methylation plays an important role in leukemogenesis of ALL, it can be targeted by 5-aza-2'-deoxycytidine (5-AZA-CdR), a potent inhibitor of DNA methylation. 5-AZA-CdR is a prodrug that is activated by deoxycytidine kinase (DCK). Leukemic cells lacking DCK are drug-resistant. In a previous phase I study, we reported that 5-AZA-CdR could induce remissions in ALL. However, some patients developed drug-resistance due to deficiency in DCK. These observations aroused our interest in 3-Deazauridine (3-DU), a CTP synthetase inhibitor that is effective against leukemic cells deficient in DCK. In this report, we observed that 3-DU enhanced the in vitro antineoplastic action of 5-AZA-CdR on human leukemic cells by increasing its incorporation into DNA. Using an optimized dose-schedule we showed that this combination could cure some mice bearing L1210 leukemia, even in the presence of a subpopulation of drug-resistant (L1210/ARA-C) leukemic cells lacking DCK. 3-DU alone also cured some mice with L1210/ARA-C leukemia. In a pilot study on 3 relapsed patients with advanced ALL, the combination of 5-AZA-CdR and 3-DU produced a marked reduction in leukemic blasts, confirming our preclinical observations. Furthermore, after several treatments with these agents all three patients developed drug-resistance to 5-AZA-CdR as determined by an in vitro drug sensitivity test. In two patients we showed by enzymatic analysis that the drug-resistance was due to deficiency in DCK. Our preclinical and clinical results provide a strong rationale to further investigate the combination of 5-AZA-CdR and 3-DU for the treatment of advanced ALL.
3-Deazauridine triggers dose-dependent apoptosis in myeloid leukemia cells and enhances retinoic acid-induced granulocytic differentiation of HL-60 cells
Int J Biochem Cell Biol 2003 Oct;35(10):1482-94.PMID:12818243DOI:10.1016/s1357-2725(03)00130-4.
Therapeutic nucleoside analogue 3-Deazauridine (DU) exerts cytotoxic activity against cancer cells by disruption of DNA synthesis resulting in cell death. The present study evaluates whether DU alone at doses 2.5-15 microM or in combination with all trans retinoic acid (RA) or dibutyryl cAMP (dbcAMP) is effective against myelogenous leukemia. The data of this study indicate that DU induces dose-dependent cell death by apoptosis in myeloid leukemia cell lines HL-60, NB4, HEL and K562 as demonstrated by cell staining or flow cytometry and agarose gel electrophoresis. 24h-treatment with DU produced dose-dependent HL-60 cell growth inhibition and dose-independent S phase arrest that was not reversed upon removal of higher doses of DU (10-15 microM). Exposition to nontoxic dose of DU (2.5 microM) for 24h followed by RA or dbcAMP and 96 h-cotreatment with DU significantly enhanced RA- but not dbcAMP-mediated granulocytic differentiation. Cell maturation was paralleled with an increase in the proportion of cells in G1 or G2+M phase. We conclude that, depending on the dose or the sequence of administration with RA, an inhibitor of DNA replication, DU triggers a process of either differentiation or apoptosis in myeloid leukemia cells.
Altered 5-azacytidine metabolism following 3-Deazauridine treatment of L5178Y and human myeloblasts
Cancer Res 1980 Nov;40(11):4000-6.PMID:6162541doi
The effect of 3-Deazauridine pretreatment on 5-azacytidine metabolism was studied in suspension cultures of L5178Y murine leukemia. A 3-hr exposure to 2 microM 3-Deazauridine followed by a 1-hr exposure to 5 microM [14C]-5-azacytidine resulted in a 2-fold increase in total intracellular 5-azacytidine accumulation compared to untreated controls. Under the same conditions, incorporation of 5-azacytidine into the acid precipitable fraction of L5178Y cells was increased 3-fold. Incorporation of 5-azacytidine into RNA increased 85% following 3-Deazauridine pretreatment, but 5-azacytidine incorporation into DNA did not change significantly. In cells pretreated with 3-Deazauridine, there was an 80% reduction of intracellular cytidine triphosphate, the natural feedback inhibitor of uridine-cytidine kinase, the rate-limiting enzyme in the phosphorylation of 5-azacytidine. Intracellular levels of 5-azacytidine triphosphate, the presumed lethal metabolite of 5-azacytidine, increased from 28.8 pmol/10(6) cells in control cells to 56.4 pmol/10(6) cells following 3-Deazauridine treatment. The sequence of 3-Deazauridine followed by 5-azacytidine demonstrated synergistic cell killing when measured by an in vitro soft-agar cloning assay. Similar biochemical alterations were also seen in human leukemic myeloblasts. It appears that 3-deazauridine-induced alterations in 5-azacytidine metabolism may account for the enhanced cytotoxicity of this drug sequence.
Antiviral and cytotoxicity evaluation of 3-nitro-3-deazauridine
Antiviral Res 1989 Dec;12(5-6):259-67.PMID:2634363DOI:10.1016/0166-3542(89)90053-3.
3-Nitro-3-deazauridine (3N-3DU) is a new synthetic nucleoside having activity against members of 5 RNA virus families including: paramyxoviruses (parainfluenza, PIV), picornaviruses (rhino-, RV), rhabdoviruses (vesicular stomatitis, VSV), togaviruses (Semliki Forest, SFV) and bunyaviruses (Punta Toro, PTV). In this report, we evaluate and compare its activity with the parent nucleoside, 3-Deazauridine (3DU) and ribavirin as drug standards. Comparison of drug activities utilizes observations of antiviral indices, which are determined by the following formula: maximum tolerated dose (MTD)/minimum inhibitory concentration (MIC). The antiviral index (AI) of 3N-3DU (AI 15.3) was comparable to ribavirin and much higher than 3DU when evaluated against PIV. The 3N-3DU was the most active of the three when tested against RV (AI 24.1), SFV (AI 76.9) or VSV (AI 50). In contrast to the RV activity, 3N-3DU (AI 0.5) and 3DU (AI less than 0.1) were less active than ribavirin (AI 1.3) when evaluated against poliovirus, type 1 (PoV). Ribavirin (AI 10.0) was more active than 3N-3DU (AI 2.4) and 3DU (AI less than 0.1) against PTV. 3N-3DU exhibited comparable toxicity to ribavirin in KB cells, was 4-fold less toxic in WISH cells and 4-fold more toxic in LLC-MK2 cells. Overall, 3N-3DU is markedly less toxic than its parent nucleoside, 3DU. It appears from this study that the structural modification of 3DU resulting from the addition of the nitro group in the 3 position of the base reduces toxicity and enhances the antiviral activity.