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- Antimetabolites
- 6-Tioguanine (6-TG)
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Tioguanine | CAS No: 154-42-7 | GMP-certified suppliers
A medication that supports remission induction and consolidation in acute nonlymphocytic leukemia by inhibiting leukemic cell proliferation through purine analogue activity.
Therapeutic categories
AntimetabolitesAntineoplastic AgentsAntineoplastic and Immunomodulating AgentsHeterocyclic Compounds, Fused-RingImmunosuppressive AgentsMyelosuppressive Agents
Generic name
Tioguanine
Molecule type
small molecule
CAS number
154-42-7
DrugBank ID
DB00352
Approval status
Approved drug
ATC code
L01BB03
Primary indications
- For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias
Product Snapshot
- Tioguanine is an oral small molecule available in tablet formulations
- It is primarily used for remission induction and consolidation in acute nonlymphocytic leukemias
- The product is approved for use in the US and Canadian markets
Clinical Overview
Tioguanine (CAS Number 154-42-7) is an antineoplastic agent classified within the purinethiones, a subgroup of purine derivatives characterized by a thioketone modification on the purine ring. It is principally indicated for the induction and consolidation of remission in patients with acute nonlymphocytic leukemia, a form of acute myeloid leukemia.
Pharmacologically, tioguanine functions as an antimetabolite targeting the S phase of the cell cycle. It acts as a 6-thiopurine analogue structurally related to hypoxanthine and guanine. Upon intracellular activation via the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase), tioguanine is converted to 6-thioguanilyl monophosphate (TGMP). TGMP accumulates at therapeutic doses and exerts its cytotoxic effect through multiple mechanisms, including inhibition of purine biosynthesis via pseudofeedback suppression of glutamine-5-phosphoribosylpyrophosphate amidotransferase and competitive blockade of IMP dehydrogenase, thereby impairing the conversion of inosinic acid to xanthylic acid.
Additionally, thioguanine nucleotides incorporate into DNA and RNA as false purine bases via phosphodiester linkage, disrupting nucleic acid function and contributing to cytotoxicity. These actions culminate in inhibition of purine nucleotide synthesis and utilization, producing a sequential blockade that impedes leukemic cell proliferation. Cross-resistance is noted with mercaptopurine, another thiopurine antimetabolite.
Key pharmacokinetic parameters include intracellular conversion and accumulation, though detailed ADME profiles vary and require consideration during therapeutic use. Safety concerns encompass myelosuppression and immunosuppression, consistent with its mechanism as a purine analogue and narrow therapeutic index. Dose monitoring is critical to balance efficacy against hematologic and hepatic toxicity.
Widely utilized in oncology and hematology, tioguanine remains a therapeutic option where purine analogue-based regimens are indicated. There are no prominent branded formulations globally recognized, but the agent’s stability, purity, and compliance with pharmacopeial standards are fundamental for API sourcing. Procurement should prioritize manufacturers with validated synthetic pathways, robust impurity profiling, and adherence to current Good Manufacturing Practices (cGMP) to ensure consistent API quality suitable for clinical and regulatory requirements.
Pharmacologically, tioguanine functions as an antimetabolite targeting the S phase of the cell cycle. It acts as a 6-thiopurine analogue structurally related to hypoxanthine and guanine. Upon intracellular activation via the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase), tioguanine is converted to 6-thioguanilyl monophosphate (TGMP). TGMP accumulates at therapeutic doses and exerts its cytotoxic effect through multiple mechanisms, including inhibition of purine biosynthesis via pseudofeedback suppression of glutamine-5-phosphoribosylpyrophosphate amidotransferase and competitive blockade of IMP dehydrogenase, thereby impairing the conversion of inosinic acid to xanthylic acid.
Additionally, thioguanine nucleotides incorporate into DNA and RNA as false purine bases via phosphodiester linkage, disrupting nucleic acid function and contributing to cytotoxicity. These actions culminate in inhibition of purine nucleotide synthesis and utilization, producing a sequential blockade that impedes leukemic cell proliferation. Cross-resistance is noted with mercaptopurine, another thiopurine antimetabolite.
Key pharmacokinetic parameters include intracellular conversion and accumulation, though detailed ADME profiles vary and require consideration during therapeutic use. Safety concerns encompass myelosuppression and immunosuppression, consistent with its mechanism as a purine analogue and narrow therapeutic index. Dose monitoring is critical to balance efficacy against hematologic and hepatic toxicity.
Widely utilized in oncology and hematology, tioguanine remains a therapeutic option where purine analogue-based regimens are indicated. There are no prominent branded formulations globally recognized, but the agent’s stability, purity, and compliance with pharmacopeial standards are fundamental for API sourcing. Procurement should prioritize manufacturers with validated synthetic pathways, robust impurity profiling, and adherence to current Good Manufacturing Practices (cGMP) to ensure consistent API quality suitable for clinical and regulatory requirements.
Identification & chemistry
| Generic name | Tioguanine |
|---|---|
| Molecule type | Small molecule |
| CAS | 154-42-7 |
| UNII | WIX31ZPX66 |
| DrugBank ID | DB00352 |
Pharmacology
| Summary | Thioguanine is an antineoplastic agent that targets purine nucleotide metabolism primarily through conversion to 6-thioguanilyic acid (TGMP), which inhibits key enzymes in de novo purine synthesis and nucleotide interconversions. Its active metabolites incorporate into DNA and RNA, disrupting nucleic acid function and leading to cytotoxicity during the S-phase of the cell cycle. Thioguanine is used for treatment of acute nonlymphocytic leukemias by impairing leukemic cell proliferation through interference with purine metabolism and nucleic acid integrity. |
|---|---|
| Mechanism of action | Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides. |
| Pharmacodynamics | Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). |
Targets
| Target | Organism | Actions |
|---|---|---|
| DNA | Humans | intercalation |
ADME / PK
| Absorption | Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) |
|---|---|
| Half-life | When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes) |
| Metabolism | Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. |
Formulation & handling
- Tioguanine is a small molecule drug administered orally in tablet form.
- It is moderately water-soluble with a low LogP, suggesting balanced hydrophilic and lipophilic properties for absorption.
- Food intake may reduce serum levels, indicating potential consideration for dosing relative to meals.
Regulatory status
| Lifecycle | The API’s primary patent protections have expired in both the US and Canada, allowing for generic competition. As a result, the market in these regions has reached a mature phase with multiple approved generic products available. |
|---|
| Markets | Canada, US |
|---|
Supply Chain
| Supply chain summary | Tioguanine is primarily manufactured by GlaxoSmithKline, with packaging handled by both GlaxoSmithKline Inc. and DSM Corp. The product has a presence mainly in North American markets, specifically Canada and the US. Given the multiple branded presentations under similar names, and the concentration in these regions, the patent status suggests either existing or potential for generic competition in these markets. |
|---|
Safety
| Toxicity | Oral, mouse: LD<sub>50</sub> = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis. |
|---|
High Level Warnings:
- Handle with appropriate personal protective equipment to prevent ingestion and skin contact
- Avoid inhalation and exposure to dust or aerosols due to potential systemic toxicity
- In case of spillage, use appropriate containment and cleaning procedures to minimize exposure risk
6-Tioguanine (6-TG) is a type of Antimetabolites
Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.
One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.
Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.
Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.
In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.
