Cyclophosphamide oxidation

Beryllium and certain compounds Cadmium and certain compounds Carbon tetrachloride Chlorambucil Cyclophosphamide Dimethylcarbamoyl chloride Dimethyl sulphate Ethylene oxide Iron dextran... 

Cyclophosphamide Cyclophosphamide, 2-[bis-(2-chloroethyl)amino]tetrahydro-2//-l,3,2-oxazaphosphorin-2-oxide (30.2.1.15), is made by reacting bis(2-chloroethyl)amine with phosphorous oxychloride, giving AA -bis-(2-chloroethyl)dichlorophosphoramide (30.2.1.14), which upon subsequent reaction with 3-aminopropanol is transformed into cyclophosphamide (30.2.1.15) [51-59],... 

Cyclophosphamide (72) was made as a latent form of nitrogen mustard with fairly low toxicity. It undergoes oxidation by microsomes in the liver and then breaks down to give much more reactive derivatives of 2,2 -dichlorodiethylamine (Scheme 3). Several aziridines are used as alkylating agents. They include triethylenemelamine (73), triaziquone (74), TEPA (triethylenephosphoramide) (75 X = O) and thio-TEPA (75 X = S). Ethylene oxide... 

Cyclophosphamide (6.31) is a nitrogen mustard used for cancer treatment (Scheme 6.9). In the body, cyclophosphamide is oxidized to aminal 6.32. Compound 6.32 opens and loses acrolein to form phosphoramide mustard (6.33). Structure 6.33 is a strong bis-electrophile and reacts readily with nucleophiles. In DNA, the nucleophile tends to be N7 of guanine, which is oriented outward into the major groove (Figure 6.6). By reacting twice, 6.33 crosslinks DNA either within the same strand (intrastrand) or across the double helix (interstrand).16... 

Unlike many DNA alkylators, cyclophosphamide shows modest selectivity for cancer cells. Healthy tissues in a patient have high levels of aldehyde dehydrogenase (ALDH). ALDH reduces the potency of cyclophosphamide by oxidizing 6.32 to 6.34, an inactive compound. Cancerous cells tend to be deficient in ALDH and more prone to damage by cyclophosphamide. 

Cyclophosphamide (Cytoxan, 8.104) is an anticancer prodrug that is oxidized by the C YP2B enzyme family in the liver (Scheme 8.27) and was first introduced back in Chapter 6. Oxidation occurs adjacent to the ring nitrogen to afford 4-hydroxycyclophosphamide (8.105), which is transported throughout the body by the circulatory system. Compound... 

Methyl methanesulphonate, ethyl methanesulfonate, ethylnitrosurea, mitomycin, or 4-nitroquinone-A-oxide for the nonmetabolic activation and benzo(a)pyrene or cyclophosphamide for the metabolic activation... 

Electrochemical oxidation of anticancer drugs ifosfamide and cyclophosphamide produced in high yield methoxylated analogues of the key hydroxy-metabolites of these oxazaphosphorine prodrugs (Scheme 19). ... 

Metabolism of the cytostatic drug cyclophosphamide (CP Fig. 1) involves hydroxylation at the C-4 position by cytochrome P450. Subsequently, a number of detoxification reactions can occur (oxidation to the keto derivative, dechloroethylation, formation of a carboxylic acid). The phosphoramide mustard resulting from spontaneous decomposition of 4-hydroxy-CP is thought to be the cytotoxic chemotherapeutic species. The chiral nature of the phosphorus atom resulted in a twofold greater therapeutic index (LDjq/EDjq) for the S-(-)-enantiomer (against the ADJ/PC6 plasma cell tumor in mice) without detectable differences in metabolism... 

The oxazophosphorine cyclophosphamide is initially oxidized to active and inactive metabolites which are secreted by the kidney [72, 73, 74, 75]. The 24 hour urinary excrehon of intact parent compound and alkylahng achvity is respectively 1-14% and 7-17% [76]. The fraction of cyclophosphamide and metabolites excreted in the urine is high and unchanged in patients with renal failure [77]. 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Tsoupras et al. used 31p nmr to detect the presence of phosphate groups in the 22-adenosinemonophosphoric ester of 2-deoxy-ecdysone and 22-phospho-2-deoxyecdysone (34). Quantitative NMR has been used in several studies. Wayne et al. used 51p nmr for quantitative analysis of organophosphorous pesticides (35). Zon et al. used NW to study chemical and microsomal oxidation of cyclophosphamide ( ), and to determine the half-life of a cyclophosphamide analogue (37). 

The nature of the products of oxidation of cyclophosphamide with Fenton s reagent has been further investigated and it now appears that the crystalline isolable product is the dimer peroxide (41). Both (41) and the hydroperoxide... 

Cyclophosphamide (36 R = H) is an effective agent for the treatment of many animal and human tumours and is oxidized in vivo by a mixed function oxidase of liver microsomes to produce a cytotoxic form of the drug. It was reported earlier that 4-hydroxy-cyclophosphamide (36 R = OH), a product of the oxidation of (36 R = H) with Fenton s reagent, was the... 

The oxidants are products of normal cellular respiration that are normally counterbalanced by an antioxidant defense system that prevents tissue destruction. The antioxidants include superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, and a-tocopherol (vitamin E). Antioxidants are ubiquitous in the body. Hy-peroxia produces toxicity by overwhelming the antioxidant system. There is experimental evidence that a number of drugs and chemicals produce lung toxicity through increasing production of oxidants (e.g., bleomycin, cyclophosphamide, nitrofurantoin, and paraquat) and/or by inhibiting the antioxidant system (e.g., carmustine, cyclophosphamide, and nitrofurantoin). ... 

In the case of azapetine (12) and nicotine (13), the iminium ion intermediate rather than the carbinolamine appears to be the form of substrate preferred by aldehyde oxidase [63-66]. On the other hand, the ring-opened aldehyde intermediate (aldophosphamide) (14) of cyclophosphamide is oxidized by the enzyme [67], although the isomeric 4-hydroxycyclophos-phamide (15) also undergoes oxidation by a soluble fraction enzyme [11]. Oxidation of the carbinolamine form to a cyclic lactam would not seem to involve nucleophilic enzyme attack, and yet we have shown that the stable pseudobase of 3-methylquinazolin-2-one (16), is an efficient substrate of aldehyde oxidase and competitively inhibits the oxidation of both quaternary and non-quatemized substrates [62]. 

Phosphorylated aldehydes (26), which are structurally related to aldo-phosphamide (14), the aldehyde metabolite of cyclophosphamide, are also substrates for aldehyde oxidase [ 168]. A good correlation was found between the ability of the compounds (26) to inhibit Nl-methylnicotinamide oxidation competitively in vitro (as a competitive substrate) and the in vivo potentiation of cyclophosphamide efficacy in mice. 

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