Pyrazofurin
(Synonyms: 吡唑霉素) 目录号 : GC37042
Pyrazofurin 是一种具有抗肿瘤活性的嘧啶核苷类似物，通过抑制尿苷5'-磷酸 (UMP) 合酶抑制细胞增殖和细胞内 DNA 合成。 Pyrazofurin 是一种活性，敏感的乳清酸-磷酸核糖基转移酶 (orotate-phosphoribosyltransferase) 抑制剂，在三种鳞状细胞癌 (SCC) 细胞系 Hep-2，HNSCC-14B 和 HNSCC-14C 的 IC50s 在 0.06-0.37 μM 之间。
Cas No.:30868-30-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pyrazofurin, a pyrimidine nucleoside analogue with antineoplastic activity, inhibits cell proliferation and DNA synthesis in cells by inhibiting uridine 5'-phosphate (UMP) synthase[1]. Pyrazofurin is an active, sensitive orotate-phosphoribosyltransferase inhibitor with IC50s between 0.06-0.37 µM in the three squamous cell carcinoma (SCC) cell lines Hep-2, HNSCC-14B and HNSCC-14C[2].
[1]. Ringer DP, et al. Alteration in de novo pyrimidine biosynthesis during uridine reversal of pyrazofurin-inhibited DNA synthesis. Neuropsychopharmacology. J Biochem Toxicol. 1991 Spring;6(1):19-27. [2]. Peters GJ, et al. Antipyrimidine effects of five different pyrimidine de novo synthesis inhibitors in three head and neck cancer cell lines. Nucleosides Nucleotides Nucleic Acids. 2018;37(6):329-339.
| Cas No. | 30868-30-5 | SDF | |
| 别名 | 吡唑霉素 | ||
| Canonical SMILES | O=C(N)C1=NNC([C@@H]2O[C@@H]([C@H]([C@H]2O)O)CO)=C1O | ||
| 分子式 | C9H13N3O6 | 分子量 | 259.22 |
| 溶解度 | Soluble in DMSO | 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 | 3.8577 mL | 19.2886 mL | 38.5773 mL |
| 5 mM | 0.7715 mL | 3.8577 mL | 7.7155 mL |
| 10 mM | 0.3858 mL | 1.9289 mL | 3.8577 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells
Adv Sci (Weinh) 2021 Mar 15;8(10):2004344.PMID:34026451DOI:10.1002/advs.202004344.
Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor Pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3. DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.
Characterization of pyrazofurin-resistant HeLa cells with amplification of UMP synthase gene
Somat Cell Mol Genet 1985 Jul;11(4):359-69.PMID:3860966DOI:10.1007/BF01534413.
Three different phenotypes have been characterized in HeLa cells that have been selected for resistance to Pyrazofurin, a potent inhibitor of the de novo pyrimidine biosynthetic enzyme UMP synthase. All of the resistant cell lines had a coordinate increase in UMP synthase activity, UMP synthase-specific mRNA, and UMP synthase gene sequences. In one of the resistant cell lines, the amplification of the UMP synthase gene is associated with a stable phenotype. There is no decrease in UMP synthase gene copy number or UMP synthase activity when these cells are grown for over six months in the absence of Pyrazofurin. Another resistant cell line that has a higher level of gene amplification when grown in the presence of Pyrazofurin loses its elevated UMP synthase activity and amplified DNA sequences with growth in the absence of the drug. A third cell line that possessed a moderate level of UMP synthase gene amplification is tenfold more resistant to Pyrazofurin than the cell line with the highest level of amplification. The extraordinary level of resistance is due to a decreased level of activity for the enzyme adenosine kinase that is required for the conversion of Pyrazofurin to its inhibitory monophosphate form.
Identification of the C-Glycoside Synthases during Biosynthesis of the Pyrazole-C-Nucleosides Formycin and Pyrazofurin
Angew Chem Int Ed Engl 2019 Nov 11;58(46):16512-16516.PMID:31518483DOI:10.1002/anie.201910356.
C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of pseudouridine-C-nucleosides has been studied, less is known about the pyrazole-C-nucleosides such as the formycins and Pyrazofurin. Herein, genome screening of Streptomyces candidus NRRL 3601 led to the discovery of the Pyrazofurin biosynthetic gene cluster pyf. In vitro characterization of gene product PyfQ demonstrated that it is able to catalyze formation of the C-glycoside carboxyhydroxypyrazole ribonucleotide (CHPR) from 4-hydroxy-1H-pyrazole-3,5-dicarboxylic acid and phosphoribosyl pyrophosphate (PRPP). Similarly, ForT, the PyfQ homologue in the formycin pathway, can catalyze the coupling of 4-amino-1H-pyrazole-3,5-dicarboxylic acid and PRPP to form carboxyaminopyrazole ribonucleotide. Finally, PyfP and PyfT are shown to catalyze amidation of CHPR to Pyrazofurin 5'-phosphate thereby establishing the latter stages of both Pyrazofurin and formycin biosynthesis.
Antiviral efficacy of Pyrazofurin against selected RNA viruses
Antiviral Res 1982 Dec;2(6):331-7.PMID:6299188DOI:10.1016/0166-3542(82)90002-x.
The antibiotic Pyrazofurin, 3-(beta-D-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide, markedly inhibited the in vitro replication of a number of RNA viruses including Rift Valley fever (RVF), Venezuelan equine encephalomyelitis (VEE), Sandfly, Pichinde, Lassa and LCM virus. Plaque formation was reduced by 80% or more with 2-10 micrograms/ml of Pyrazofurin while 2 micrograms/ml reduced by 1000-fold the yield of Lassa and LCM virus in a yield reduction assay. In vivo, Pyrazofurin failed to protect mice and guinea pigs against a lethal challenge with VEE and Pichinde virus, respectively. On the other hand, Pyrazofurin caused a slight increase in the mean time to death of mice infected with RVF virus.
Synthesis and biological activity of certain nucleoside and nucleotide derivatives of Pyrazofurin
J Med Chem 1986 Feb;29(2):268-78.PMID:3950908DOI:10.1021/jm00152a016.
A number of nucleoside and nucleotide derivatives of 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (Pyrazofurin, 1) were prepared and tested for their antiviral and cytostatic activity in cell culture. Treatment of 1 with benzyl bromide gave 4-O-benzylpyrazofurin (4). Methylation of 4 with CH2N2 and subsequent removal of the benzyl group by catalytic hydrogenation provided 1-methylpyrazofurin (8). Direct methylation of 1 with CH3I furnished 4-O-methylpyrazofurin (6). Dehydration of the pentaacetylpyrazofurin (9) with phosgene furnished 4-acetoxy-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1-acetylpyrazol e-5-carbonitrile (10). A similar dehydration of the precursor tetraacetyl derivative of 4 gave the corresponding carbonitrile, which on deprotection and subsequent treatment with hydroxylamine furnished 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-carboxamidoxime (13). Treatment of the tetraacetyl derivative of 4 with Lawesson's reagent and subsequent deacetylation furnished a mixture of 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-thiocarboxamide (15) and the corresponding nitrile derivative (16). Phosphorylation of unprotected 4 with POCl3 and subsequent debenzylation of the intermediate 17 gave Pyrazofurin 5'-phosphate (18), which provided the first chemical synthesis of 18. Similar phosphorylation of 4 with POCl3 and quenching the reaction mixture with either EtOH or MeOH, followed by debenzylation, furnished the 5'-O-(ethyl phosphate) (19b) and 5'-O-(dimethyl phosphate) (20b) derivatives of Pyrazofurin. DCC-mediated cyclization of 17, followed by debenzylation, gave Pyrazofurin 3',5'-(cyclic)phosphate (21b). The NAD analogue 23b was also prepared by the treatment of 17 with an activated form of AMP in the presence of AgNO3. The structural assignment of 7,8, and 20a were made by single-crystal X-ray analysis, and along with Pyrazofurin, their intramolecular hydrogen bond characteristics have been studied. All of these compounds were tested in Vero cell cultures against a spectrum of viruses. Compounds 18 and 23b were active at concentrations very similar to Pyrazofurin but are less toxic to the cells than Pyrazofurin. Compounds 19b, 20b, and the 3',5'-(cyclic)phosphate 21b are less active than 1. Compounds 18, 19b, 20b, and 23b also exhibited significant inhibitory effects on the growth of L1210 and P388 leukemias and Lewis lung carcinoma cells in vitro, whereas B16 melanoma cells were less sensitive to growth inhibition by these compounds. Pyrazofurin derivatives modified at the 1-, 4-, or 5-position showed neither antiviral nor cytostatic activity in cell culture.