10-propargyl-10-deazaaminopterin

10-Propargyl-10-deazaaminopterin

10-Propargyl-10-deazaaminopterin (also known as PDX) is a potent antifolate compound that has been studied for its potential use in cancer therapy. It is a derivative of aminopterin, a compound that was one of the first antifolates used in the treatment of cancer.

Chemical Structure and Properties

10-Propargyl-10-deazaaminopterin is a structural analog of methotrexate, another well-known antifolate. The modification involves the substitution of a propargyl group at the 10-position and the removal of a nitrogen atom from the pteridine ring, hence the name "deazaaminopterin."

The chemical formula of 10-propargyl-10-deazaaminopterin is C₂₀H₂₂N₈O₅. This modification enhances its ability to inhibit dihydrofolate reductase (DHFR), an enzyme critical for the synthesis of tetrahydrofolate, which is necessary for the synthesis of purines and thymidylate, and thus for DNA replication and cell division.

Mechanism of Action

10-Propargyl-10-deazaaminopterin works by inhibiting the enzyme dihydrofolate reductase (DHFR). By blocking this enzyme, the drug prevents the conversion of dihydrofolate to tetrahydrofolate, leading to a depletion of thymidylate and purine nucleotides. This results in the inhibition of DNA synthesis and cell division, particularly affecting rapidly dividing cancer cells.

Clinical Applications

Research has shown that 10-propargyl-10-deazaaminopterin has significant antitumor activity in various preclinical models. It has been studied in the treatment of several types of cancer, including leukemia, lymphoma, and solid tumors.

The compound has been found to be more potent than methotrexate in some studies, with a different toxicity profile, which may offer advantages in certain clinical settings. However, its clinical use is still under investigation, and it is not yet approved for widespread use.

Pharmacokinetics

The pharmacokinetics of 10-propargyl-10-deazaaminopterin involve its absorption, distribution, metabolism, and excretion. Like other antifolates, it is administered intravenously and has a distribution pattern that allows it to reach high concentrations in tumor tissues. Its metabolism and excretion are primarily hepatic and renal, respectively.

Side Effects

As with other antifolates, the side effects of 10-propargyl-10-deazaaminopterin can include myelosuppression, mucositis, and gastrointestinal disturbances. The specific side effect profile may vary depending on the dose and schedule of administration.

Also see

• Aminopterin
• Methotrexate
• Antifolate
• Dihydrofolate reductase
• Cancer chemotherapy