Cyclophosphamide, derivatives

Roberts JD, Hacker MP, McCormack JJ, et al. 1983. Toxicologic and efficacy studies of ASTA Z-7557 A sulfonatoethylthio cyclophosphamide derivative [Abstract], Proc Am Assoc Cancer Res 24 988. 

Whitehouse NW, Beck FWJ. 1975. Irritancy of cyclophosphamide-derived aldehydes (acrolein, chloracetaldehyde) and their effect on lymphocyte distribution in vivo Protective effect of thiols and bilsulphite ions. Agents Actions 5 541-548. 

Diazacyclophosphamides (87, 88) and oxaazacyclophosphamidic chlorides (89) have been used as reagents for the determination of the optical purity and absolute configuration of amines and alcohols. These have been readily determined by H and P NMR data of the cyclophosphamide derivatives that are formed in these reactions. NMR data has also been used (together with other data) in the structural determinations of diorganotin bis-O-alkyl phosphonates (90), of N-(l-oxo-l-phospha-2,6,7-trioxabicyclo- [2.2.2]octane-4-car-... 

Hirano, T., Ringsdorf, H. and Zaharko, D.Z. (1980) Antitumour activity of monomeric and polymeric cyclophosphamide derivatives compared with in vitro hydrolysis. Cancer Res. 40 2263-2267. 

Judy KD, OUvi A, Buahin KG, Domb A, Epstein JI, Colvin OM, Brem H. Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas. J Neurosurg 1995 82 481—486. 

A number of cyclophosphamide derivatives of purine and pyrimidine nucleosides have been synthesized by Okruszek and Verkade and our laboratory, respectively. Among these derivatives, compounds 86a, and 86b, which are isomeric at phosphorus, were active against KB tumor cells in culture with EC50 values of 1.1 and 1.2 pg/mL, respectively.66... 

Exposure to the fetus in the first 2 weeks after conception may have an all or nothing effect (i.e., could destroy the embryo or have no ill effect). Exposure during the period of organogenesis (18 to 60 days postconception) may result in structural anomalies (e.g., methotrexate, cyclophosphamide, diethylstilbestrol, lithium, retinoids, thalidomide, certain antiepileptic drugs, and coumarin derivative). 

New derivatives and analogues of cyclophosphamide (35 R = H) have been reported80 and the diastereoisomeric jY-l-phenylethyl derivatives (35 ... 

R = PhCHMe) have been prepared and distinguished by n.m.r. spectroscopy.31 Attempts to prepare 7V-aryl derivatives of cyclophosphamide by cyclization of the phosphoramides (36) proved unsuccessful.32 Although this type of reaction has proved to be of great value in the preparation of perhydro-l,3,2-oxazaphosphorines and 1,3,2-oxazaphospholidines when NaOEt, NaOH, or NaH are employed as reagent, in this instance the bis(chloroethyl)amide side-chain presents a further possible reaction site. However, steric effects, also considered as an explanation for instances of failure of the reaction (see Organophosphorus Chemistry , Vol. 7, p. Ill) may be operating adversely. 

Novel nitroxide malonate methanofullerenes (Fig. 1.3), thanks to the presence of nitroxide radicals and fullerene moiety, are able to protect cells from toxic side effects of cyclophosphamide (Gubskaya et al., 2007). Experiments were carried out on mice, in which leukemia P-388 was transplanted. Cyclophosphamide or fullerene individually injected did not increase the average life span of the animals, while the combination of the anticancer drug and nitroxide fullerene derivative resulted in the survival of 70% animals, classifying these compounds as promising modifiers of biological reaction for tumor therapy. 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

The nitrogen mustard analogues are nitrogen derivatives of sulfur mustard, used as poison gas in World War I. Agents include cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifos-famide, uramustine and estramustine. 

Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabofically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide. 

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... 

The B block may consist of a water-soluble polymer, for example, poly(aspartic acid) P(Asp), that is rendered hydrophobic by the chemical conjugation of a hydrophobic drug (Yokoyama et al., 1992, 1993, 1996 Nakanishi et al., 2001), or is formed through the association of two oppositely changed polyions (polyion complex micelles) (Hatada etal., 1995,1998 Kataoka etal., 1996). Drugs used to couple the B block include cyclophosphamide, doxorubicin, cisplatin, pyrene, and iodine derivative of benzoic acid (Kwon and Kataoka, 1995 Trubetskoy et al., 1997 Yu etal., 1998). 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

Lelieveld P, Vanputten LM. 1976. Biologic activity of two derivatives and six possible metabolites of cyclophosphamide (NSC-26271). Cancer Treat Rep 60 373-379. 

---