Raltitrexed
[CAS 112887-68-0]

Identification

• Classification: API >> Antineoplastic agents >> Antimetabolite antineoplastic
• Name: Raltitrexed
• Synonyms: (S)-2-[(1-{5-[Methyl-(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-amino]-thiophen-2-yl}-methanoyl)-amino]-pentanedioic acid
• Molecular Formula: C₂₁H₂₂N₄O₆S
• Molecular Weight: 458.49
• CAS Registry Number: 112887-68-0
• EC Number: 652-997-2
• SMILES: CC1=NC2=C(C=C(C=C2)CN(C)C3=CC=C(S3)C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)N1

Properties

• Density: 1.5$+/-$0.1 g/cm³ Calc.^*
• Solubility: DMSO 82 mg/mL, Water $lessThan$1 mg/mL (Expl.)
• Index of refraction: 1.692 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Germ cell mutagenicity	Muta.	2	H341
Reproductive toxicity	Repr.	2	H361
Reproductive toxicity	Repr.	1B	H360
Acute toxicity	Acute Tox.	3	H301

Discovery and Applications

Raltitrexed is a synthetic antifolate antineoplastic agent developed for the treatment of colorectal cancer. It is a structural and functional analogue of folate that acts as a direct and specific inhibitor of thymidylate synthase, an enzyme essential for DNA synthesis and cellular replication. By blocking this enzyme, raltitrexed disrupts the production of thymidine nucleotides, leading to inhibition of DNA synthesis and ultimately cell death, particularly in rapidly dividing tumor cells.

The development of raltitrexed arose from efforts in medicinal chemistry to create more selective antifolate drugs compared to earlier agents such as methotrexate. While methotrexate inhibits dihydrofolate reductase and affects multiple folate-dependent pathways, raltitrexed was designed to directly target thymidylate synthase, thereby achieving a more focused mechanism of action. This selectivity was intended to improve antitumor efficacy while reducing some of the systemic toxicities associated with broader antifolate inhibition.

Structurally, raltitrexed contains a heterocyclic quinazoline-like core linked to glutamic acid moieties that allow it to mimic the natural substrate of folate-dependent enzymes. The molecule is transported into cells via reduced folate carriers and then polyglutamated by folylpolyglutamate synthetase. This intracellular modification increases its retention within cells and enhances its inhibitory potency against thymidylate synthase. The polyglutamated forms bind more tightly to the enzyme, resulting in sustained suppression of DNA synthesis.

The mechanism of action of raltitrexed involves tight binding to thymidylate synthase at its folate-binding site. This enzyme catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, a critical step in the synthesis of DNA. Inhibition of this reaction leads to depletion of thymidine nucleotides and accumulation of deoxyuridine triphosphate, resulting in DNA damage and cell cycle arrest, particularly during the S phase of cell division.

Raltitrexed was developed during the expansion of antifolate research programs in the late 20th century, when there was significant interest in designing enzyme-specific inhibitors for cancer therapy. Its design was based on detailed understanding of folate metabolism and enzyme structure, enabling rational drug design approaches that improved specificity for thymidylate synthase.

Clinically, raltitrexed has been used primarily in the treatment of advanced colorectal cancer, particularly in patients who cannot tolerate or are not suitable for fluoropyrimidine-based therapies such as 5-fluorouracil. It has also been investigated in other solid tumors, including mesothelioma, where folate pathway inhibition may have therapeutic benefit. The drug is administered intravenously and is typically given in cycles due to its effects on rapidly dividing normal tissues as well as tumor cells.

The pharmacokinetics of raltitrexed are characterized by relatively long intracellular retention due to polyglutamation, which allows sustained enzyme inhibition even after plasma levels decline. It is eliminated primarily via renal excretion, and dosing must be adjusted in patients with impaired kidney function.

Adverse effects of raltitrexed are consistent with its mechanism of action and include myelosuppression, gastrointestinal toxicity, and hepatotoxicity. Because it interferes with DNA synthesis, it also affects normal rapidly dividing tissues such as bone marrow and gastrointestinal epithelium.

Overall, raltitrexed is a targeted antifolate chemotherapeutic agent that exerts its antitumor effects through selective inhibition of thymidylate synthase. Its development reflects advances in rational drug design aimed at improving specificity within the folate metabolic pathway, and it remains an important option in the treatment of certain solid tumors, particularly colorectal cancer.

References

2026. Discovery of quinazoline-based derivatives as novel autophagy inhibitors in pancreatic cancer. Medicinal Chemistry Research.
DOI: 10.1007/s00044-026-03533-6

2026. Relative Clinical Efficacy and Safety of Second- or Later-Line Treatments for Advanced and Metastatic Gastric Cancer: A Rapid Review and Network Meta-Analysis. Journal of Gastrointestinal Cancer.
DOI: 10.1007/s12029-026-01407-z

2026. Construction and external validation of a prognostic model for survival in hepatocellular carcinoma patients undergoing transarterial chemoembolization: a multicenter retrospective cohort study. World Journal of Surgical Oncology.
DOI: 10.1186/s12957-025-04182-6