molecular formula C7H15Cl2N2O2P B1669514 Cyclophosphamide CAS No. 50-18-0

Cyclophosphamide

Cat. No.: B1669514
CAS No.: 50-18-0
M. Wt: 261.08 g/mol
InChI Key: CMSMOCZEIVJLDB-UHFFFAOYSA-N
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Description

Cyclophosphamidee is a synthetic compound belonging to the class of alkylating agents, specifically nitrogen mustards. It is widely used in chemotherapy and immunosuppressive therapy. Cyclophosphamidee is known for its effectiveness in treating various types of cancers, including lymphomas, leukemias, and solid tumors, as well as autoimmune diseases .

Mechanism of Action

Target of Action

Cyclophosphamide is an alkylating agent that primarily targets DNA . It prevents cell division by cross-linking DNA strands and decreasing DNA synthesis . This makes it particularly effective against rapidly dividing cells, such as cancer cells .

Mode of Action

This compound is a prodrug that must be metabolized in the liver to form the active metabolites, phosphoramide mustard and acrolein . Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions . This cross-linking leads to cell death as it prevents the normal functioning of DNA, including replication and transcription .

Biochemical Pathways

The metabolism of this compound involves a complex bioactivation pathway. Hepatic enzymes first convert this compound to hydroxythis compound, which is then subsequently metabolized to aldophosphamide . The majority of the antineoplastic effects of this compound are due to the phosphoramide mustard formed from the metabolism of the drug .

Pharmacokinetics

This compound undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein . This compound appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration .

Result of Action

The result of this compound’s action is the death of rapidly dividing cells, such as cancer cells . This is due to the DNA cross-linking caused by its active metabolite, phosphoramide mustard . It also possesses potent immunosuppressive activity , which can lead to side effects such as myelosuppression .

Action Environment

Environmental factors can influence the action of this compound. For example, a study showed that this compound at an environmentally relevant concentration influenced the life history and protein profiles of Daphnia magna, a small planktonic crustacean . This suggests that the environment can influence the efficacy and stability of this compound, although more research is needed in this area.

Safety and Hazards

Cyclophosphamide can sometimes cause a decrease in your blood count, liver problems, hair loss, and mouth ulcers . There’s also a slightly increased risk of certain types of cancer, particularly bladder cancer . It is toxic if swallowed and may cause genetic defects, cancer, and harm to the unborn child .

Future Directions

Cyclophosphamide has shown great promise in further improving response rates in early-stage patients . Given the heterogeneity within triple negative tumors, molecular subtypes with variable genomic makeup and chemo sensitivities have been identified and will likely aid in further clinical developmental therapeutics .

Biochemical Analysis

Biochemical Properties

Cyclophosphamide is an alkylating agent that damages cancer cell DNA, inhibiting growth and division . It also affects healthy cells, leading to severe cytotoxicity . It is metabolized in the liver to form the active metabolite 4-hydroxythis compound . This metabolite interferes with the growth of susceptible rapidly proliferating malignant cells .

Cellular Effects

This compound has a significant impact on various types of cells and cellular processes. It can cause low white blood cell counts, loss of appetite, vomiting, hair loss, and bleeding from the bladder . Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis .

Molecular Mechanism

This compound works by interfering with the duplication of DNA and the creation of RNA . It is believed to work by forming cross-links with DNA strands and decreasing DNA synthesis . It is a cell cycle phase nonspecific agent .

Temporal Effects in Laboratory Settings

In the days following the administration of this compound, the number of white blood cells in the blood will be much lower than normal before they rise in time for the stem cell harvest . This means that the risk of infection is increased and immunity is too low to fight an infection .

Dosage Effects in Animal Models

In animal models, a single administration of this compound induces memory impairment . The effects of this compound vary with different dosages. For example, mice treated with this compound at 40 or 200 mg/kg 1 day before training showed significant impairment of 24-hour memory retention .

Metabolic Pathways

This compound is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system . These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells .

Transport and Distribution

This compound is inactive until it undergoes hepatic transformation to form 4-hydroxythis compound, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard .

Subcellular Localization

The subcellular localization of this compound and its metabolites is primarily in the liver, where it is metabolized to its active form . It is also distributed throughout the body and can affect cells in various tissues due to its systemic administration .

Preparation Methods

Synthetic Routes and Reaction Conditions: Cyclophosphamidee is synthesized through a multi-step process. The initial step involves the reaction of 2-chloroethylamine hydrochloride with phosphorus oxychloride to form 2-chloroethylphosphorodiamidic chloride. This intermediate is then reacted with N,N-bis(2-chloroethyl)amine to produce cyclophosphamide .

Industrial Production Methods: In industrial settings, this compound is typically produced through a lyophilization process. This involves dissolving this compound in a suitable solvent, followed by aseptic filtration and removal of the solvent under aseptic conditions. The resulting this compound powder is then filled into pharmaceutical containers .

Comparison with Similar Compounds

Cyclophosphamidee’s versatility and effectiveness make it a valuable compound in both clinical and research settings.

Properties

IUPAC Name

N,N-bis(2-chloroethyl)-2-oxo-1,3,2λ5-oxazaphosphinan-2-amine
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InChI

InChI=1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12)
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InChI Key

CMSMOCZEIVJLDB-UHFFFAOYSA-N
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Canonical SMILES

C1CNP(=O)(OC1)N(CCCl)CCCl
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Molecular Formula

C7H15Cl2N2O2P
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Related CAS

6055-19-2 (monohydrate)
Record name Cyclophosphamide [USP:INN]
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DSSTOX Substance ID

DTXSID5020364
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Molecular Weight

261.08 g/mol
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Physical Description

Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45 °C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent., White odorless solid; Liquefies upon loss of crystallization water; Darkens on light exposure; [ICSC] White odorless crystalline solid; [MSDSonline], Solid, FINE WHITE CRYSTALLINE POWDER.
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Boiling Point

336 °C
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Flash Point

113 °C c.c.
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Solubility

10 to 50 mg/mL at 73 °F (NTP, 1992), Soluble. 1-5 g/100 mL at 23 °C, 1 in 25 parts water, 1 in 1 parts alcohol, Slightly soluble in benzene, carbon tetrachloride; very slightly soluble in ether and acetone, Soluble in chloroform, dioxane and glycols and insoluble in carbon tetrachloride and carbon disulfide., In water, 40,000 ppm @ 20 °C, 1.51e+01 g/L, Solubility in water, g/l at 20 °C: 40 (moderate)
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Density

1.48 g/cm³
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Vapor Pressure

0.0000445 [mmHg], Vapor pressure, Pa at 25 °C: 0.006 (calculated)
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Mechanism of Action

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations., The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, & imidazole groups. The chemotherapeutic & cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents & may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine & pyrimidine bases of DNA- particularly, the 1 & 3 nitrogens of adenine, the 3 nitrogen of cytosine, & the 6 oxygen of guanine- also may be alkylated, as will be the phosphate atoms of the DNA chains & amino & sulfhydryl groups of proteins. /Alkylating agents/, Cyclophosphamide can be used to cause immunologically mediated regression of the immunogenic, cyclophosphamide-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice (B6D2F1 (C57BL/6 x DBA/2) females). In order to cause tumor regression it was necessary to give cyclophosphamide (125-200 mg/kg of body wt, iv shortly before or shortly after tumor implantation. Regardless of whether cyclophosphamide was given before or after tumor implantation, tumor regression was associated with the presence in the spleen of an incr number of Lyt-2+ T-cells capable of passively transferring immunity to tumor bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after day 12 of tumor growth. Because the therapeutic effect of cyclophosphamide could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of cyclophosphamide is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by cyclophosphamide., These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has long latency of onset (8-13 hr) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors., The most likely mechanism by which cyclophosphamide augments immune responses relates to preferential elimination of suppressor and relative sparing of effector and helper cells. Thus, precursors and mature murine suppressor cells are very sensitive to cyclophosphamide whereas the mature effector cells are relatively insensitive ... . Cyclophosphamide induced immunological regression of murine leukemia is reversed by the infusion of normal spleen cells as a source of precursors of suppressor cells ... . Memory and helper T cells are relatively resistant to the cytotoxic effect of cyclophosphamide ... . NK activity against YAC lymphoma targets by non T and non B cells is depressed by cyclophosphamide ... .
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Color/Form

LIQUEFIES ON LOSS OF ITS WATER OF CRYSTALLIZATION, Crystalline solid

CAS No.

50-18-0, 6055-19-2
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Melting Point

106 to 113 °F (NTP, 1992), 48-49, 49.5-53 °C, 41 - 45 °C, 49.5 - 53 °C
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Description The International Chemical Safety Cards (ICSCs) are data sheets intended to provide essential safety and health information on chemicals in a clear and concise way. The primary aim of the Cards is to promote the safe use of chemicals in the workplace.
Explanation Creative Commons CC BY 4.0

Synthesis routes and methods I

Procedure details

3-aminopropanol (2.1 g, 0.028 mol) and N-methylmorpholine (12.9 eq) are placed into a three-necked flask and stirred at room temperature. After cooling the mixture in the flask, POCl3 (4.3 g, 0.028 mol) is slowly dropped into the mixture. After adding POCl3, the mixture in the flask is stirred at room temperature for 15 hours. After that, bis(2-chloroethyl)amine hydrochloride] (5 g, 0.028 mol) is added into the mixture in the flask. The mixture in the flask is heated to about 40° C. and stirred for 6 hours. (The conversion yield determined with HPLC is about 10.0%.)
Quantity
2.1 g
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Name
Quantity
4.3 g
Type
reactant
Reaction Step Two
Name
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Three
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Four

Synthesis routes and methods II

Procedure details

Bis(2-chloroethyl)amine hydrochloride (5 g, 0.028 mol) is put into a 100 mL two-necked flask, and N,N′-Dimethylpiperazine (7.1 eq) is added into the flask. After cooling the flask and the reactants therein to about 4° C., POCl3 (4.49 g, 1.04 eq) is slowly dropped into the flask, and the mixture in the flask is stirred at room temperature for 5 hours. After that, the mixture in the flask is cooled to about 4° C., and 3-aminopropanol (2.1 g, 1.0 eq) is slowly dropped into the flask for 3 hours. After adding 3-aminopropanol into the flask, the mixture in the flask is stirred at room temperature for 15 hours. (The conversion yield determined with HPLC is about 11.84%.)
Quantity
5 g
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Two
Name
Quantity
4.49 g
Type
reactant
Reaction Step Three
Quantity
2.1 g
Type
reactant
Reaction Step Four
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Five

Synthesis routes and methods III

Procedure details

A solution of bis(2-chloroethyl)phosphoramidic dichloride (10 mmol) in ethyl acetate (100 mL) is added dropwise to a solution of commercial 3 methylamino-1-phenyl-1-propanol (10 mmol) and triethylamine (20 mmol) in ethyl acetate (100 mL) at rt. After stirring at rt for 3 days, the salts are filtered off and the combined filtrates are concentrated under vacuum. The crude product is purified by column chromatography on silica.
Quantity
10 mmol
Type
reactant
Reaction Step One
Name
methylamino-1-phenyl-1-propanol
Quantity
10 mmol
Type
reactant
Reaction Step One
Quantity
20 mmol
Type
reactant
Reaction Step One
Quantity
100 mL
Type
solvent
Reaction Step One
Quantity
100 mL
Type
solvent
Reaction Step One

Retrosynthesis Analysis

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Feasible Synthetic Routes

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