Thioguanine

Purine antimetabolite CAS# 154-42-7

Thioguanine

Catalog No. BCC2220----Order now to get a substantial discount!

Product Name & Size Price Stock
Thioguanine:50mg $40.00 In stock
Thioguanine:100mg $68.00 In stock
Thioguanine:250mg $160.00 In stock
Thioguanine:500mg $280.00 In stock
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Chemical structure

Thioguanine

3D structure

Chemical Properties of Thioguanine

Cas No. 154-42-7 SDF Download SDF
PubChem ID 2723601 Appearance Powder
Formula C5H5N5S M.Wt 167.19
Type of Compound N/A Storage Desiccate at -20°C
Synonyms 6-TG
Solubility DMSO : 10 mg/mL (59.81 mM; Need ultrasonic and warming)
Chemical Name 2-amino-3,7-dihydropurine-6-thione
SMILES C1=NC2=C(N1)C(=S)N=C(N2)N
Standard InChIKey WYWHKKSPHMUBEB-UHFFFAOYSA-N
Standard InChI InChI=1S/C5H5N5S/c6-5-9-3-2(4(11)10-5)7-1-8-3/h1H,(H4,6,7,8,9,10,11)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Thioguanine

DescriptionAnticancer and immunosuppressive agent often used to treat immune disorders and leukemia. Displays cytotoxic and antineoplastic properties; disrupts cytosine methylation by DNA methyltransferases after incorporation into DNA. Selectively kills BRCA2-defective tumors in a xenograft model. Also facilitates proteasome-mediated degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1).

Protocol

Cell Assay [3]
Treatments consists of 3 thiopurines (azathioprine, 6-mercaptopurine, and 6-thioguanine) at each of 6 concentrations (0.468, 0.937, 1.875, 3.750, 7.500, and 15.000 μM). Each thiopurinee is dissolved in DMSO solution to achieve a concentration of 10 mg/mL. Sterile filtered maintenance medium is used to further dilute each thiopurine solution to each of the 6 treatment concentrations. Twenty-four hours after the hepatocytes are plated on 96-well culture[3].

References:
[1]. Chuang SJ, et al. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2. Sci Rep. 2018 Feb 15;8(1):3102. [2]. Wang H, et al. 6-Thioguanine perturbs cytosine methylation at the CpG dinucleotide site by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo. Biochemistry. 2009 Mar 17;48(10):2290-9. [3]. LaDuke KE, et al. Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes. Am J Vet Res. 2015 Jul;76(7):649-55.

Thioguanine Dilution Calculator

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Thioguanine Molarity Calculator

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Preparing Stock Solutions of Thioguanine

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 5.9812 mL 29.9061 mL 59.8122 mL 119.6244 mL 149.5305 mL
5 mM 1.1962 mL 5.9812 mL 11.9624 mL 23.9249 mL 29.9061 mL
10 mM 0.5981 mL 2.9906 mL 5.9812 mL 11.9624 mL 14.953 mL
50 mM 0.1196 mL 0.5981 mL 1.1962 mL 2.3925 mL 2.9906 mL
100 mM 0.0598 mL 0.2991 mL 0.5981 mL 1.1962 mL 1.4953 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Thioguanine

Thioguanine is a purine antimetabolite widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis) and organ transplant recipients.

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References on Thioguanine

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.[Pubmed:28258828]

Lancet Oncol. 2017 Apr;18(4):515-524.

BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated Thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1.0-17.9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m(2) once per day and methotrexate 20 mg/m(2) once per week, targeted to a leucocyte count of 1.5-3.0 x 10(9) cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4.6 years (IQR 3.1-6.1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0.81 per 100 fmol/mug DNA increase, 95% CI 0.67-0.98; p=0.029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0.0001). INTERPRETATION: Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. FUNDING: Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.

Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity?[Pubmed:28264514]

Molecules. 2017 Feb 28;22(3). pii: molecules22030379.

6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug's overall photoreactivity. However, 6-Thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-Thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution. The experimental results are complemented with time-dependent density functional calculations that include solvent dielectric effects by means of a reaction-field solvation model. UVA excitation results in the initial population of the S(2)(pipi*) state, which is followed by ultrafast internal conversion to the S(1)(npi*) state and then intersystem crossing to the triplet manifold within 560 +/- 60 fs. A small fraction (ca. 25%) of the population that reaches the S(1)(npi*) state repopulates the ground state. The T(1)(pipi*) state decays to the ground state in 1.4 +/- 0.2 mus under N(2)-purged conditions, using a 0.2 mM concentration of 6-Thioguanine, or it can sensitize singlet oxygen in 0.21 +/- 0.02 and 0.23 +/- 0.02 yields in air- and O(2)-saturated solution, respectively. This demonstrates the efficacy of 6-Thioguanine to act as a Type II photosensitizer. N9-glycosylation increases the rate of intersystem crossing from the singlet to triplet manifold, as well as from the T(1)(pipi*) state to the ground state, which lead to a ca. 40% decrease in the singlet oxygen yield under air-saturated conditions. Enhanced vibronic coupling between the singlet and triplet manifolds due to a higher density of vibrational states is proposed to be responsible for the observed increase in the rates of intersystem crossing in 6-Thioguanine upon N9-glycosylation.

Is there a role for thioguanine therapy in IBD in 2017 and beyond?[Pubmed:28276819]

Expert Rev Gastroenterol Hepatol. 2017 May;11(5):473-486.

INTRODUCTION: Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of Thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'Thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose Thioguanine is an alternative to other therapies that are either parenteral or expensive.

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.[Pubmed:28339328]

J Clin Oncol. 2017 May 20;35(15):1730-1736.

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell Thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 +/- 107.1 v 220.6 +/- 121.6; P = .5), with dairy versus without (220.1 +/- 87.8 v 216.3 +/- 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 +/- 119.7 v 195.5 +/- 82.3 v 174.8 +/- 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

6-Thioguanine reactivates epigenetically silenced genes in acute lymphoblastic leukemia cells by facilitating proteasome-mediated degradation of DNMT1.[Pubmed:21239472]

Cancer Res. 2011 Mar 1;71(5):1904-11.

Thiopurines including 6-Thioguanine ((S)G), 6-mercaptopurine, and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). (S)G is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that (S)G treatment results in reactivation of epigenetically silenced genes in T leukemia cells. Bisulfite genomic sequencing revealed that (S)G treatment universally elicited demethylation in the promoters and/or first exons of the genes that were reactivated. (S)G treatment also attenuated the expression of histone lysine-specific demethylase 1 (LSD1), thereby stimulating lysine methylation of the DNA methylase DNMT1 and triggering its degradation via the ubiquitin-proteasomal pathway. Taken together, our findings reveal a previously uncharacterized but vital mechanistic link between (S)G treatment and DNA hypomethylation.

6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance.[Pubmed:20631063]

Cancer Res. 2010 Aug 1;70(15):6268-76.

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-Thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy.

6-Thioguanine perturbs cytosine methylation at the CpG dinucleotide site by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo.[Pubmed:19236003]

Biochemistry. 2009 Mar 17;48(10):2290-9.

Thiopurines are among the most successful chemotherapeutic agents for treating a number of human diseases including acute lymphoblastic leukemia. The mechanisms through which the thiopurines elicit their cytotoxic effects remain unclear. We postulate that the incorporation of 6-Thioguanine into the CpG site may perturb the methyltransferase-mediated cytosine methylation at this site, thereby interfering with the epigenetic pathways of gene regulation. To gain biochemical evidence for this hypothesis, we assessed, by using a restriction enzyme digestion coupled with LC-MS/MS method, the impact of 6-Thioguanine on cytosine methylation mediated by two DNA methyltransferases, human DNMT1 and bacterial HpaII. Our results revealed that the incorporation of 6-Thioguanine into the CpG site could affect the methylation of the cytosine residue by both methyltransferases and the effect on cytosine methylation is dependent on the position of 6-Thioguanine with respect to the cytosine to be methylated. The presence of 6-Thioguanine at the methylated CpG site enhanced the DNMT1-mediated methylation of the opposing cytosine in the complementary strand, whereas the presence of 6-Thioguanine at the unmethylated CpG site abolished almost completely the methylation of its 5' adjacent cytosine by both DNMT1 and HpaII. We further demonstrated that the treatment of Jurkat T cells, which were derived from acute lymphoblastic leukemia, with 6-Thioguanine could result in an appreciable drop in the level of global cytosine methylation. These results showed that 6-Thioguanine, after being incorporated into DNA, may perturb the epigenetic pathway of gene regulation.

Description

6-Thioguanine (Thioguanine; 2-Amino-6-purinethiol) is an anti-leukemia and immunosuppressant agent, acts as an inhibitor of SARS and MERS coronavirus papain-like proteases (PLpros) and also potently inhibits USP2 activity, with IC50s of 25 μM and 40 μM for Plpros and recombinant human USP2, respectively.

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