31645-39-3

Basic information

• Product Name: Palifosfamide
• Synonyms: N,N'-BIS(2-CHLOROETHYL)PHOSPHORODIAMIDATE;Isophosphamide mustard;palifosfamide;N,N'-Bis(2-chloroethyl)phosphorodiamidic acid;Ifosforamide mustard;Ipam;N,N'-Di-(2-chloroethyl)phosphorodiamidic acid;N1,N2-Bis(2-chloroethyl)phosphoric acid diamide
• CAS NO: 31645-39-3
• Molecular Formula: C₄H₁₁Cl₂N₂O₂P
• Molecular Weight: 221.02
• Mol File: 31645-39-3.mol
• Article Data: 12

Chemical Properties

• Melting Point: 106-107 ºC
• Boiling Point: 341.5 °C at 760 mmHg
• Flash Point: 160.4 °C
• Appearance: /
• Density: 1.411
• Vapor Pressure: 1.45E-05mmHg at 25°C
• Refractive Index: 1.497
• Solubility: ≥22.1 mg/mL in DMSO; insoluble in EtOH; ≥19.4 mg/mL in H2O with gentle warming and ultrasonic
• PKA: 0.79±0.50(Predicted)
• CAS DataBase Reference: Palifosfamide(CAS DataBase Reference)
• NIST Chemistry Reference: Palifosfamide(31645-39-3)
• EPA Substance Registry System: Palifosfamide(31645-39-3)

Safety Data

• Hazardous Substances Data: 31645-39-3(Hazardous Substances Data)

Usage

Description

Palifosfamide is an active metabolite of the DNA alkylating agent ifosfamide, formed through hydroxylation by hepatic cytochrome P450 (CYP) isoforms. It exhibits cytotoxicity to L1210 and CCRF-CEM cancer cells at a concentration of 100 μM and demonstrates tumor growth reduction in various murine and rat cancer models.

Uses

Used in Oncology:
Palifosfamide is used as a cytotoxic agent for the treatment of various types of cancer. Its cytotoxic properties make it effective against L1210 and CCRF-CEM cancer cells, and it has been shown to reduce tumor growth in murine Lewis lung carcinoma, L1210 leukemia, and rat Yoshida ascitic sarcoma models. This makes it a promising candidate for cancer therapy, particularly in combination with other treatments to enhance efficacy and overcome drug resistance.

InChI:InChI=1/C4H11Cl2N2O2P/c5-1-3-7-11(9,10)8-4-2-6/h1-4H2,(H3,7,8,9,10)

Upstream product

• 70772-68-8 Phenylphosphorsaeureester-N,N'-(2-chlorethyl)diamid 
• 84681-49-2 benzyl N,N’-bis(2-chloroethyl)phosphorodiamidate 
• 120144-70-9 aldoifosfamide 
• 50892-10-9 4-Hydroxyifosfamide 
• 132682-98-5 glufosfamide 
• 870-24-6 2-chloroethanamine hydrochloride 

Relevant articles and documents

Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged us a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.

Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy

The tumor microenvironment in chondrosarcoma (CHS), a chemo- and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug‐delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables hypoxia‐responsive drug release. In a previous work, ICF05016 was identified as efficient proteoglycan-targeting hypoxia-activated prodrug in a human extraskeletal myxoid chondrosarcoma model in mice and a first study of the structure-activity relationship of the QA function and the alkyl linker length was conducted. Here, we report the second part of the study, namely the modification of the nitro-aromatic trigger and the position of the proteoglycan-targeting ligand at the aromatic ring as well as the nature of the alkylating mustard. Synthetic approaches have been established to functionalize the 2-nitroimidazole ring at the N-1 and C-4 positions with a terminal tertiary alkyl amine, and to perform the phosphorylation step namely through the use of an amine borane complex, leading to phosphoramide and isophosphoramide mustards and also to a phosphoramide mustard bearing four 2-chloroethyl chains. In a preliminary study using a reductive chemical activation, QA-conjugates, except the 4-nitrobenzyl one, were showed to undergo efficient cleavage with release of the corresponding mustard. However N,N,N-trimethylpropylaminium tethered to the N-1 or C-4 positions of the imidazole seemed to hamper the enzymatic reduction of the prodrugs and all tested compounds featured moderate selectivity toward hypoxic cells, likely not sufficient for application as hypoxia-activated prodrugs.

TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS

The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.