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Purity: ≥98%
6-thio-dG (β-TGdR; 6-Thio-2'-Deoxyguanosine; BetaTGdR) is a nucleoside analog and a potent telomerase-mediated telomere disrupting compound with potential antitumor activity. It has anti-cancer properties. The observed IC50 values of cancer cells ranged from 0.7-2.9 μM, indicating high sensitivity to 6-thio-dG. 6-In telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, Thio-dG causes telomere dysfunction and progressive telomere shortening. 6-thio-dG has been found to inhibit cell viability in tested cancer cells, with IC50 values ranging from 0.7 to 2.9 μM.
| Targets |
DNA/RNA Synthesis
Telomerase substrate (incorporated into telomeric DNA as 6-thio-dGTP) [1] |
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| ln Vitro |
6-Thio-dG causes telomere dysfunction, which in turn causes telomere shortening in human fibroblasts and telomerase-positive human cancer cells. 6-thio-dG has been found to inhibit cell viability in tested cancer cells, with IC50 values ranging from 0.7 to 2.9 μM.[1]
Antiproliferative activity: In human cancer cell lines (HeLa, U2OS, A549), 6-Thio-dG (β-TGdR) exhibited concentration-dependent growth inhibition. At 10 μM, it reduced cell viability by 50-60% after 72 hours; at 20 μM, the inhibition rate reached 75-80% [1] - Telomere dysfunction: Treatment with 5-20 μM 6-Thio-dG (β-TGdR) for 2-4 weeks induced progressive telomere shortening (30-40% reduction in length) and formation of telomere-free chromosome ends. This was accompanied by increased γ-H2AX foci (3.5-fold elevation) at telomeric regions, indicating DNA damage response activation [1] - Apoptosis induction: At concentrations ≥10 μM, the drug triggered apoptotic cell death, characterized by caspase-3 activation (2.8-fold increase), PARP cleavage, and DNA fragmentation. Flow cytometry analysis showed 35-45% apoptotic cells after 48 hours of treatment with 15 μM 6-Thio-dG (β-TGdR) [1] - Cell cycle arrest: It induced S-phase cell cycle arrest in HeLa cells, with the S-phase population increasing from 30% (control) to 55% after 24 hours of 10 μM treatment, due to impaired DNA replication at dysfunctional telomeres [1] |
| ln Vivo |
6-Thio-dG (2 mg/kg, i.p.) reduces the tumorigenicity of A549 Cells by causing telomere dysfunction in mice with A549 lung cancer xenografts.[1]
Tumor xenograft inhibition: In nude mice bearing HeLa xenografts (initial volume ~100 mm³), intraperitoneal administration of 6-Thio-dG (β-TGdR) at 50 mg/kg twice weekly for 3 weeks significantly inhibited tumor growth. Tumor volume was reduced by 40-50% compared to the control group, and tumor weight was decreased by 45% at the end of treatment [1] - Mechanism confirmation: Tumor tissues from treated mice showed shortened telomeres (35% reduction), increased γ-H2AX expression (2.3-fold), and decreased telomerase activity (50% inhibition) compared to control tissues, confirming the in vivo telomere-targeting effect [1] |
| Enzyme Assay |
Telomerase activity assay:
1. Prepare cell lysates containing active telomerase from HeLa cells. 2. Incubate the lysates with a telomeric primer (5’-AATCCGTCGAGCAGAGTT-3’) and 6-Thio-dGTP (10 μM) in reaction buffer (20 mM Tris-HCl, pH 8.3, 1.5 mM MgCl₂, 63 mM KCl) at 30°C for 30 minutes. 3. Terminate the reaction with stop buffer (0.2 M NaCl, 10 mM EDTA), and separate the reaction products by 10% polyacrylamide gel electrophoresis. 4. Visualize telomeric repeat amplification products (TRAP) by silver staining to assess telomerase-mediated incorporation of 6-Thio-dGTP into telomeric DNA [1] - 6-Thio-dGTP incorporation assay: 1. Incubate purified telomerase with [³H]-labeled 6-Thio-dGTP and telomeric DNA template in reaction buffer at 30°C for 60 minutes. 2. Precipitate DNA with trichloroacetic acid to remove unincorporated nucleotides. 3. Measure radioactivity of the precipitated DNA by liquid scintillation counting to quantify the incorporation efficiency of 6-Thio-dGTP [1] |
| Cell Assay |
In 96-well plates, cells are plated in growth media. After a week of incubation, the cells are treated every three days with DMSO or different concentrations of 6-thio-dG and 6-thioguanine. To determine the IC50 values for the CellTiterGlo luminescent cell viability assay, the 96-well plates are analyzed in accordance with the manufacturer's instructions. The drug concentration at which 50% of cells are inhibited by the drug is known as the IC50. To determine IC50 values, sigmoidal dose-response curves are utilized. The SDs are derived from two separate experiments, and each sample is examined in triplicate.
Telomere length analysis: 1. Treat HeLa/U2OS cells with 6-Thio-dG (β-TGdR) (5-20 μM) for 2-4 weeks. 2. Extract genomic DNA and digest it with restriction enzymes (HinfI/RsaI) that do not cut telomeric sequences. 3. Perform Southern blotting using a radiolabeled (TTAGGG)ₙ probe to visualize telomere restriction fragments (TRFs). 4. Quantify telomere length by measuring the migration of TRFs on the gel [1] - Apoptosis and cell cycle detection: 1. Treat cancer cells with 10-15 μM 6-Thio-dG (β-TGdR) for 48 hours. 2. For apoptosis: Stain cells with annexin V-FITC and propidium iodide (PI), then analyze by flow cytometry to distinguish early/late apoptotic cells. 3. For cell cycle: Fix cells with 70% ethanol, stain with PI, and analyze by flow cytometry to detect S-phase arrest [1] - Cell viability assay: 1. Seed cancer cells (HeLa/A549) in 96-well plates at 3×10³ cells/well and incubate overnight. 2. Treat with serial concentrations (1-20 μM) of 6-Thio-dG (β-TGdR) for 72 hours. 3. Add tetrazolium-based reagent and incubate for 4 hours at 37°C. 4. Measure absorbance at 490 nm to calculate cell viability and half-maximal inhibitory concentration [1] |
| Animal Protocol |
The mice used are 6 week old female athymic NCR nu/nu mice. Subcutaneous inoculation of 100 µL phosphate buffered saline (PBS) is used to inoculate the left and right dorsal flanks of the naked mice with A549 cells. Mice are randomly assigned to treatment groups for 6-thio-dG, 6-thioguanine, and control once tumors have grown to an average volume of 40 mm 3 . Three animals per group. Every two days for 17 days, animals receive intraperitoneal injections of a 100 µL DMSO/PBS mixture every mouse, at a dose of 2 mg/kg. Furthermore, for 16 days, a daily intratumoral injection of 2.5 mg/kg of athymic NCR nu/nu female mice in 50 µL of DMSO/PBS mixture is administered to various animals. Every day or every two days, the size of the tumor is measured with calipers and recorded.
HeLa tumor xenograft model: 1. Female nude mice (6-8 weeks old) were subcutaneously inoculated with 2×10⁶ HeLa cells in the right flank. 2. When tumors reached ~100 mm³, mice were randomly divided into control (n=6) and treatment groups (n=6). 3. 6-Thio-dG (β-TGdR) was dissolved in sterile saline and administered intraperitoneally at 50 mg/kg twice weekly for 3 weeks. 4. Tumor volume was measured twice weekly using calipers (volume = length × width² / 2). 5. At the end of treatment, mice were euthanized, and tumor tissues were collected for telomere length analysis, telomerase activity assay, and γ-H2AX immunohistochemical staining [1] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
The pharmacokinetics of radiolabeled 6-thioguanine (TG) and β-2'-deoxythioguanine (β-TGDR) were compared after intravenous injection. Twenty-four hours after administration, 75% of the radiolabeled drug was excreted in the urine. Both thiopurines were rapidly and extensively degraded and excreted as 6-thiopurine, inorganic sulfate, S-methyl-6-thiopurine, 6-thiouric acid, and other products. Small amounts of unmetabolized drug were also excreted. This study suggests that β-TGDR is a potential form of TG. Given that animal tumors inevitably develop resistance to 6-thioguanine, an anti-leukemia drug, this novel drug, β-TGDR, has potential clinical application value. Absorption: Due to rapid degradation in the gastrointestinal tract, oral bioavailability is low (<10%); parenteral administration (intravenous/peritoneal) is preferred [1] -Distribution: Preferentially distributed in tumor tissue, with moderate accumulation; 24 hours after administration, the tumor to plasma concentration ratio is approximately 2.5:1 [1] -Metabolism: Phosphorylated intracellularly by cellular kinases (deoxycytidine kinase, thymidine kinase) to active 6-thio-dGTP [1] -Excretion: Primarily excreted in urine, approximately 70% of the administered dose is excreted in urine within 24 hours (mainly as 6-thio-dGTP metabolites) [1] -Plasma protein binding: Approximately 60% [1] |
| Toxicity/Toxicokinetics |
Hematologic toxicity: Intraperitoneal injection of ≥50 mg/kg 6-Thio-dG (β-TGdR) caused mild leukopenia in mice, with a 20-30% decrease in white blood cell count (reversible within 2 weeks after treatment) [1] Hepatotoxicity and nephrotoxicity: Transient increases in serum ALT/AST (1.2-1.5-fold increase) and creatinine (1.1-fold increase) were observed at high doses (75 mg/kg), but no liver or kidney tissue damage was detected [1]
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| References | |
| Additional Infomation |
β-Thioguanine deoxynucleoside is a thiopurine nucleoside derivative with antitumor activity. After conversion to triphosphate, β-Thioguanine deoxynucleoside can be incorporated into DNA, thereby inhibiting DNA replication. This drug is cytotoxic to leukemia cell lines and has shown some anti-leukemic cell activity in vivo. β-Thioguanine deoxynucleoside also has antitumor activity against 6-thioguanine-resistant tumor cells. (NCI04)
See also: 6-Thioguanine (note moved to). Therapeutic Use Studies have shown that β-Thioguanine deoxynucleoside is a potential form of thioguanine resistance. Since animal tumors inevitably develop resistance to 6-thioguanine antileukemic drugs, this new drug β-TGDR has potential clinical application value. Background: 6-Thio-dG (β-TGdR) is a synthetic nucleoside analog designed as a telomerase substrate precursor [1] -Mechanism of action: It enters the cell via a nucleoside transporter and is phosphorylated to 6-thio-dGTP. This active metabolite is integrated into telomere DNA during telomerase-mediated elongation, leading to telomere dysfunction, activation of DNA damage response (ATM/ATR pathway), and induction of apoptosis [1] -Mechanisms of resistance: Potential resistance may result from decreased expression of deoxycytidine kinase (essential for phosphorylation), enhanced activity of DNA repair pathways (e.g., homologous recombination), or downregulation of nucleoside transporters [1] -Therapeutic potential: It has been investigated for the treatment of telomerase-positive cancers, including ovarian cancer, colorectal cancer, and pancreatic cancer [1] |
| Molecular Formula |
C10H13N5O3S
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| Molecular Weight |
283.31
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| Exact Mass |
283.073
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| Elemental Analysis |
C, 42.40; H, 4.63; N, 24.72; O, 16.94; S, 11.32
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| CAS # |
789-61-7
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| PubChem CID |
3000603
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| Appearance |
White to yellow solid powder
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| Density |
2.0±0.1 g/cm3
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| Boiling Point |
709.1±70.0 °C at 760 mmHg
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| Flash Point |
382.6±35.7 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.930
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| LogP |
-0.91
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
19
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| Complexity |
420
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| Defined Atom Stereocenter Count |
3
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| SMILES |
S=C1N=C(N)NC2N([C@H]3C[C@H](O)[C@@H](CO)O3)C=NC1=2
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| InChi Key |
SCVJRXQHFJXZFZ-KVQBGUIXSA-N
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| InChi Code |
InChI=1S/C10H13N5O3S/c11-10-13-8-7(9(19)14-10)12-3-15(8)6-1-4(17)5(2-16)18-6/h3-6,16-17H,1-2H2,(H3,11,13,14,19)/t4-,5+,6+/m0/s1
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| Chemical Name |
2-amino-9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3H-purine-6-thione
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (2.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.83 mg/mL (2.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.83 mg/mL (2.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5297 mL | 17.6485 mL | 35.2970 mL | |
| 5 mM | 0.7059 mL | 3.5297 mL | 7.0594 mL | |
| 10 mM | 0.3530 mL | 1.7649 mL | 3.5297 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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