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 . Palifosfamide is formed through hydroxylation of ifosfamide by various hepatic cytochrome P450 (CYP) isoforms. It is cytotoxic to L1210 and CCRF-CEM cancer cells when used at a concentration of 100 μM. Palifosfamide (100 mg/kg per day) reduces tumor growth in murine Lewis lung carcinoma and L1210 leukemia models, as well as a rat Yoshida ascitic sarcoma model.

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

Upstream product

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

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.

SYNTHESIS AND FORMULATIONS OF SALTS OF ISOPHOSPHORAMIDE MUSTARD AND ANALOGS THEREOF

Disclosed herein are formulations and methods of manufacture of compounds of formula (E):wherein X and Y independently represent leaving groups; and A+ is an ammonium cation.