Ifosfamide | Alkylating Agent | CAS 3778-73-2 | Antineoplastic

Product Name: Ifosfamide
CAS No.: 3778-73-2
Chemical Name: N,3-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide
Molecular Formula: C₇H₁₅Cl₂N₂O₂P
Appearance: White crystalline powder
Solubility: Soluble in water
Stability: Relatively stable when dry; solutions are prepared immediately before use

1. Introduction

Ifosfamide is a cytostatic antineoplastic drug from the group of alkylating compounds, a structural analog of cyclophosphamide. It is a prodrug requiring metabolic activation in the liver. It is used in the chemotherapy of various solid tumors and hematologic malignancies.

Ifosfamide belongs to the oxazaphosphorine group and has a broad spectrum of antitumor activity. Its mechanism of action is based on DNA alkylation, leading to disruption of DNA structure and function, inhibition of replication, and ultimately tumor cell death. To prevent urotoxicity (hemorrhagic cystitis) associated with acrolein formation, ifosfamide is always used together with mesna (sodium 2-mercaptoethanesulfonate).

2. Chemical Structure & Synthesis

Ifosfamide is an isomer of cyclophosphamide, differing in the position of one of the chloroethyl groups (attached to the endocyclic nitrogen atom rather than the exocyclic one as in cyclophosphamide).

Synthesis: Ifosfamide is synthesized from N-(2-chloroethyl)-N'-(3-hydroxypropyl)ethylenediamine and phosphoryl chloride, followed by oxidation.

3. Mechanism of Action

Ifosfamide is a prodrug and is activated in the liver by the cytochrome P450 system (primarily CYP3A4 and CYP2B6) through hydroxylation at the C4 carbon atom of the oxazaphosphorine ring. The resulting 4-hydroxyifosfamide exists in equilibrium with its tautomer – aldoifosfamide. Aldoifosfamide spontaneously decomposes to form the active alkylating metabolite – ifosfamide mustard (ifosforamide mustard) and acrolein.

• Ifosfamide mustard forms covalent bonds with nucleophilic groups of DNA (primarily at the N7 position of guanine), leading to DNA crosslinking, disruption of its template function, inhibition of DNA and RNA synthesis, and cell apoptosis

• Acrolein is a toxic metabolite responsible for the development of hemorrhagic cystitis

4. Pharmacokinetics

Administered intravenously. Widely distributed in the body. Metabolized in the liver. Excreted primarily by the kidneys as metabolites and partially unchanged.

5. Applications

Ifosfamide is used as monotherapy or as part of combination chemotherapy for various malignancies:

• Soft tissue and bone sarcomas (osteosarcoma, Ewing's sarcoma)

• Testicular cancer (germ cell tumors)

• Lymphomas (non-Hodgkin lymphomas, Hodgkin's lymphoma – in refractory cases)

• Lung cancer (small cell and non-small cell)

• Cervical cancer, ovarian cancer

• Breast cancer

• Other solid tumors in children and adults

6. Conclusion

Ifosfamide is an important alkylating antineoplastic drug with proven efficacy in several malignancies. Its use requires mandatory co-administration of mesna for urotoxicity prevention, as well as careful monitoring of kidney function, hematopoiesis, and potential neurotoxic effects. Despite its toxicity, ifosfamide remains a valuable component of many chemotherapy regimens.