6-Thioguanine

Target of Action

6-Thioguanine primarily targets the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) . This enzyme plays a crucial role in the purine salvage pathway, which is essential for DNA and RNA synthesis. Additionally, this compound has been found to inhibit the human deubiquitinating protease USP2 , which plays a critical role in tumor cell survival .

Mode of Action

This compound competes with hypoxanthine and guanine for HGPRTase and is converted into 6-thioguanilyic acid (TGMP) . TGMP reaches high intracellular concentrations at therapeutic doses . The TGMP, along with its diphosphate (TGDP) and triphosphate (TGTP) forms, are collectively named This compound nucleotides (6-TGN) . These 6-TGNs are cytotoxic to cells by incorporating into DNA during the synthesis phase (S-phase) of the cell cycle and inhibiting the GTP-binding protein (G protein) Rac1, which regulates the Rac/Vav pathway .

Biochemical Pathways

The biochemical pathways affected by this compound primarily involve the purine salvage pathway and the Rac/Vav pathway . The incorporation of 6-TGN into DNA disrupts normal DNA synthesis and function, leading to cell death. The inhibition of the G protein Rac1 disrupts the Rac/Vav pathway, further contributing to the cytotoxic effects of this compound .

Pharmacokinetics

This compound is administered orally and has a bioavailability of 30% (range 14% to 46%) . It is metabolized intracellularly, and its elimination half-life is approximately 80 minutes (range 25–240 minutes) . The drug is excreted in urine .

Result of Action

The primary result of this compound’s action is the induction of cell death in rapidly dividing cells, such as cancer cells . This is achieved through the disruption of DNA synthesis and function, as well as the inhibition of the Rac/Vav pathway . These actions make this compound effective in the treatment of various forms of leukemia .

Action Environment

The action of this compound can be influenced by various environmental factors. For instance, the deamination reaction of this compound has been found to be more feasible in the presence of an additional water molecule . Additionally, the drug’s efficacy can be affected by the pH of the stomach, as it is expected that the entire dosages of thioguanine can be dissolved rapidly in the gastric fluids due to the low pH (~ pH 1–2) . Furthermore, the drug’s action can be influenced by genetic factors, as people with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects .

Pharmacological Profile

Mechanism of Action
6-Thioguanine functions as an antimetabolite, primarily inhibiting DNA synthesis by incorporating into nucleic acids, particularly DNA. This incorporation disrupts the replication process, leading to cell death in rapidly dividing tumor cells. Evidence indicates that 6-TG is more effective in younger, rapidly growing tumor populations compared to older ones, highlighting the importance of timing in treatment regimens .

Pharmacokinetics
The pharmacokinetics of 6-TG have been extensively studied. It is metabolized by guanase and xanthine oxidase, with higher blood levels observed post-intravenous administration compared to oral dosing. Studies show that repeated doses lead to significant incorporation of 6-TG into DNA, particularly in bone marrow cells .

Clinical Applications

Cancer Treatment
this compound has been utilized in various types of cancer, particularly hematological malignancies such as acute leukemia and lymphomas. Its efficacy has been noted in patients with specific genetic profiles, particularly those with homozygous deletions of the methylthioadenosine phosphorylase (MTAP) gene. These tumors are often resistant to other therapies but may respond favorably to 6-TG when combined with methylthioadenosine (MTA), which protects normal tissues from toxicity while allowing higher doses of 6-TG .

Case Study: Leukemia Treatment

A retrospective study involving 30 patients with Crohn's Disease who failed conventional immunosuppression demonstrated the efficacy of 6-TG as a third-line treatment. The median dose was 40 mg daily over 21.5 months, with an initial clinical response in 60% of patients . This study underscores the drug's potential beyond oncology into inflammatory conditions.

Combination Therapies

Research suggests that combining this compound with other agents can enhance its therapeutic effects. For instance, combinations with methotrexate or pralatrexate have shown promising results against MTAP-deficient tumors. The synergistic effects observed in xenograft models indicate a potential for developing more effective treatment protocols .

Safety and Toxicity

While 6-TG is effective, it is not without risks. Hepatotoxicity remains a concern, particularly in long-term use. In the previously mentioned study on Crohn's Disease patients, some experienced abnormal liver function tests during treatment; however, these were mostly mild and transient . Monitoring liver function during therapy is crucial for patient safety.

Summary Table of Applications

Biochemical Properties

6-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 . It is ribosylated and phosphorylated by the same pathway as natural purine bases .

Cellular Effects

This compound has been shown to have cytotoxic effects on cells. It is incorporated into DNA during the synthesis phase (S-phase) of the cell cycle, stopping normal development and division . It also inhibits the GTP-binding protein (G protein) Rac1, which regulates the Rac/Vav pathway .

Molecular Mechanism

The molecular mechanism of this compound involves its conversion to 6-thioguanilyic acid (TGMP) via the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). TGMP is then further metabolized to form this compound nucleotides (6-TGN). These 6-TGN are cytotoxic to cells by incorporation into DNA during the synthesis phase (S-phase) of the cell and through inhibition of the GTP-binding protein (G protein) Rac1 .

Temporal Effects in Laboratory Settings

The effects of this compound in laboratory settings can vary over time. For instance, a study showed that mean this compound nucleotide levels were higher among patients in clinical remission, with a pooled difference of 63.37 pmol/8 × 10 8 red blood cells .

Dosage Effects in Animal Models

In animal models, the effects of this compound can vary with different dosages. A study demonstrated the efficacy of low dose this compound treatment on low-mutation melanoma in a pre-clinical mouse model .

Metabolic Pathways

This compound is catabolized via two pathways. One route is through the deamination by the enzyme guanine deaminase to 6-thioxanthine, which has minimal anti-neoplastic activity, then by oxidation by xanthine oxidase of the thioxanthine to thiouric acid .

Transport and Distribution

This compound is transported and distributed within cells and tissues. It is converted to 6-thioguanilyic acid (TGMP) by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and reaches high intracellular concentrations at therapeutic doses .

Subcellular Localization

The subcellular localization of this compound involves its incorporation into DNA during the synthesis phase (S-phase) of the cell cycle . This suggests that this compound is localized in the nucleus where DNA replication occurs.

Voies synthétiques et conditions réactionnelles

Tioguanine peut être synthétisée en utilisant la 2,9-diacétyl guanine ou la 2-acétyl guanine comme matières de départ. La réaction implique la sulfuration de ces composés avec du pentasulfure de phosphore dans une solution de pyridine, avec un léger catalyseur . Cette méthode offre des conditions de réaction douces, une opération simple et un rendement élevé pouvant atteindre 75 % .

Méthodes de production industrielle

La production industrielle de la tioguanine suit des voies synthétiques similaires, mais à plus grande échelle. Le procédé implique l'utilisation d'anhydride thiophosphorique et de solution de pyridine, avec un contrôle minutieux des conditions réactionnelles pour assurer un rendement élevé et une pureté .

Types de réactions

Tioguanine subit diverses réactions chimiques, notamment :

Désamination : La réaction de désamination de la tioguanine avec l'eau, les ions hydroxydes et les formes protonées a été étudiée de manière approfondie.

Oxydation : Tioguanine peut être oxydée pour former des métabolites toxiques, contribuant à ses effets cytotoxiques.

Réactifs et conditions communs

Désamination : Les ions hydroxydes et l'eau sont des réactifs courants utilisés dans la désamination de la tioguanine.

Oxydation : Des espèces réactives de l'oxygène, telles que l'oxygène singulet et les radicaux superoxydes, sont impliquées dans l'oxydation de la tioguanine.

Principaux produits formés

Désamination : La désamination de la tioguanine conduit à la formation de divers intermédiaires et produits, selon les conditions réactionnelles.

Oxydation : L'oxydation de la tioguanine conduit à la formation de métabolites toxiques qui peuvent être incorporés dans l'ADN.

Applications de la recherche scientifique

Tioguanine a plusieurs applications de recherche scientifique, notamment :

Chimie : Utilisée comme composé modèle dans des études sur les analogues de la purine et leurs propriétés chimiques.

Biologie : Étudiée pour ses effets sur la synthèse de l'ADN et de l'ARN, ainsi que pour son rôle dans le métabolisme cellulaire.

Médecine : Principalement utilisé dans le traitement de diverses formes de leucémie.

Industrie : Utilisé dans le développement de nouveaux agents antinéoplasiques et d'autres composés thérapeutiques.

Mécanisme d'action

Tioguanine exerce ses effets en entrant en compétition avec l'hypoxanthine et la guanine pour l'enzyme hypoxanthine-guanine phosphoribosyltransférase (HGPRTase). Elle est convertie en acide 6-thioguanilyique, qui atteint des concentrations intracellulaires élevées à des doses thérapeutiques . Le composé est incorporé dans l'ADN pendant la phase de synthèse, ce qui conduit à des effets cytotoxiques . De plus, la tioguanine inhibe la protéine de liaison au GTP Rac1, qui régule la voie Rac/Vav .

Tioguanine fait partie de la famille des thiopurines, qui comprend la mercaptopurine et l'azathioprine . Comparée à ces composés, la tioguanine a une efficacité plus élevée et une action plus rapide . son utilisation est limitée par des inquiétudes concernant l'hépatotoxicité et d'autres effets secondaires .

Composés similaires

Mercaptopurine : Un autre analogue de la purine utilisé dans le traitement de la leucémie et d'autres affections.

Azathioprine : Un prodrug de la mercaptopurine, utilisé comme immunosuppresseur dans la transplantation d'organes et les maladies auto-immunes.

Les propriétés uniques de la tioguanine, telles que son incorporation dans l'ADN et l'inhibition de voies moléculaires spécifiques, en font un composé précieux dans les milieux de recherche et cliniques .

6-Thioguanine (6-TG) is a purine analog that has been utilized in the treatment of various hematological malignancies, particularly acute myeloid leukemia (AML). Since its approval in the 1960s, research has expanded to explore its biological activity beyond oncology, revealing significant effects in conditions like diabetic retinopathy and psoriasis. This article delves into the biological activity of 6-TG, supported by case studies, data tables, and comprehensive research findings.

6-TG exerts its effects primarily through the inhibition of purine metabolism and DNA synthesis. It gets incorporated into DNA, replacing guanine, which leads to the disruption of DNA replication and ultimately induces apoptosis in rapidly dividing cells, such as cancer cells and activated lymphocytes. This mechanism is particularly relevant in the treatment of leukemias and autoimmune diseases.

Key Mechanisms:

• Inhibition of DNA synthesis : 6-TG is metabolized to thioguanine nucleotides (TGNs), which interfere with DNA replication.
• Induction of apoptosis : Primarily observed in activated T lymphocytes, where it triggers programmed cell death.
• Immunosuppressive effects : Reduction in peripheral blood lymphocytes and total leukocyte counts.

1. Treatment of Psoriasis

A notable study involving 20 patients with moderate to severe plaque-type psoriasis demonstrated that 6-TG significantly improved disease severity. After six months of treatment:

• 12 patients were completely cleared of disease.
• 6 showed marked improvement .
• 2 did not respond .

Biopsy results indicated a reduction in keratinocyte proliferation and inflammation, correlating with clinical improvement. The therapy also led to a significant decrease in circulating lymphocytes by an average of 42% after two months .

2. Anti-Angiogenic Activity in Diabetic Retinopathy

Recent research highlighted the anti-angiogenic properties of 6-TG in diabetic retinopathy models. In vitro studies with human umbilical vein endothelial cells (HUVECs) exposed to high glucose levels showed:

• Marked reduction in tube formation at concentrations as low as 5 µM .
• In vivo studies demonstrated that diabetic mice treated with 6-TG exhibited reduced retinal vascular alterations, as confirmed by fluorescein angiography .

3. Efficacy in Leukemia Treatment

Comparative studies have shown that 6-TG is more effective than its counterpart, 6-mercaptopurine, particularly in reducing the risk of isolated central nervous system relapse. However, it carries a higher risk of severe adverse effects, including veno-occlusive disease .

Toxicity and Side Effects

While 6-TG has demonstrated efficacy across various conditions, its use is associated with several toxicities:

• Risk of infections due to immunosuppression.
• Development of liver complications such as veno-occlusive disease.
• Mutagenic potential leading to G→A mutations .

Summary Table: Clinical Findings

Research Findings

A variety of studies have investigated the pharmacokinetics and biological effects of 6-TG:

• Pharmacokinetics : Blood levels were higher post-intravenous administration compared to oral doses, indicating better bioavailability and incorporation into DNA .
• Mutagenicity Studies : Research indicated that both 6-TG and its metabolites are mutagenic in human cell lines, raising concerns about long-term use .
• Immunological Effects : A decrease in circulating leukocytes was noted alongside clinical improvements in autoimmune conditions .