A-nitrosoureas

H2NCON(NO)Me, KOH, DME, H2O, 0°, 75% yield. This method generates diazomethane in situ. A -Methyl-A -nitrosourea is a proven carcinogen. 

Heterocyclic analogs of A-nitrosoureas as anticancer drugs 97CRV829. 

Lomustine (2-chlorethyl-3 cyclohexyl-1 -nutrosourea, CCNU, Fig 3) is a nitrosourea for oral application. It is used for the treatment of Hodgkin s lymphomas, brain tumors and bronchial carcinomas at a dose of 3.5 mg/kg (130 mg/m2) repeated in 6-8 weeks intervals. 

Poly(DL-lactide) was used as the excipient in microspheres of CCNU, a nitrosourea, prepared by a solvent evaporation procedure (96,97). PLA-CCNU microspheres 3.0 pm in diameter were injected i.v. and leukemia cell survival was determined by spleen colony assay. A 100-fold decrease in leukemia cell survival was observed with the microspheres in both spleen and liver compared to untreated controls. Promising results were also obtained with Lewis lung carcinoma in mice. These studies showed that 2- to 4-ym microspheres were preferentially targeted to the lungs. 

For cyclopropanation of alkenes devoid of base-sensitive functional groups a one-pot procedure has been developed [649]. In this procedure diazomethane is generated in a biphasic system from A-methyl-A-nitrosourea and potassium hydroxide in the presence of a palladium complex (e.g. Pd(acac)2, (PhCN)2PdCl2, or Pd[P(OPh)3]4) and the alkene. In this way the handling of diazomethane is elegantly avoided. 

Some diazoalkanes cyclopropanate olefins in the absence of any catalyst [658-660]. Thus, for instance, upon generation from A -cyclopropyl-A -nitrosourea at 0 °C diazocyclopropane spontaneously cyclopropanates methylenecyclopropanes [658]. Thermal, uncatalyzed cyclopropanations of unactivated olefines with aryldiazome-thanes can already occur at only slightly elevated temperatures (e.g. at 80 °C with 1-naphthyldiazomethane [661]). Henee, for enantioselective cyclopropanations with a chiral catalyst, low reaction temperatures should be chosen to minimize product formation via the uncatalyzed pathway. 

The answer is d. (Hardman, pp 1242-1243.) Streptozocin is an alkylating agent with the capacity to cross-link DNA, thereby inhibiting its synthesis. It is a nitrosourea-like antibiotic that contains a glucosamine moiety that allows it to be selectively taken up by the p cells of the islets of Langerhans. Consequently, it can be useful in treating metastatic islet cell carcinoma. 

Ethylene sulfide Ethylene thiourea 2-Ethylhexyl aerylate Ethyl methanesulfonate A-Ethyl-A-nitrosourea... 

Druker BJ. Cireumventing resistanee to kinase-inhibitor therapy. N EnglJMed 2006 354 2594-2596. Bradeen HA, Bide CA, O Hare T et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an A-ethyl-A-nitrosourea (ENU)-based mutagenesis sereen high effieaey of drug eombinations. Blood 2006 108 2332-2338. 

Swann, PF. Magee, P.N. (1968) Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by A-methyl-A -nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. Biochem. J., 110, 39-47... 

Groups of female Fischer 344 rats, six to eight weeks old, were either left untreated (group A) or received a single intravesicular instillation of 0.3 mg A-methyl-A-nitroso-urea (group B), six intravesicular instillations of 2.5 mg methyl methanesulfonate at 14-day intervals (group C) or sequential treaments with 0.3 mg A-methyl-A-nitrosourea followed by six intravesicular instillations of 2.5 mg methyl methanesulfonate at 14-day intervals (group D). The numbers of rats with bladder tumours were (A) 0/25, (B) 7/29 (24%), (C) 2/27 (7%) and (D) 19/33 (58%) (Tudor et al., 1984). 

Warren, W, Clark, J.P, Gardner, E., Harris, G, Cooper, C.S. Lawley, PD. (1990) Chemical induction of thymomas in AKR mice interaction of chemical carcinogens and endogenous murine leukemia viruses. Comparison of W-methyl-A-nitrosourea and methyl methane-sulphonate. Mol. Carcinog., 3, 126-133... 

The inhibitory effect of sitosterol (33) on colon tumor formation in rats treated with the carcinogen A-methyl-A-nitrosourea (MNU) has been studied, and it has been demonstrated that compound 33 nullified in part the effect of this direct-acting carcinogen on the colon [44]. This suggested that phytosterols may have a protective dietary action to retard colon tumor formation. 

In the other method (h), the effluent from the HPLC column was mixed with a mixture of concentrated H2S04, glacial acetic acid, and KI solution, and the mixture was passed through a Teflon reaction coil kept immersed in a 70-80°C water bath. As before, the carrier gas, introduced after denitrosation, carried the liberated NO through a series of cold traps into the TEA. The system worked well with aqueous mobile phases but not with normal-phase solvents. Response for NPRO was linear from 3.5 to 900 ng injection, with a coefficient of variation of 3-5%. The temperature of the reaction coil seemed to be critical for the determination of A-nitro-samines, which are difficult to denitrosate with HI. While a temperature of 23°C was adequate for the denitrosation of NPRO and several A-nitrosoureas, a much higher temperature (up to 70°C) was required for comparable response from NDMA or NPYR. 

Methyl-4-nitropyridine N-oxide, 2310 A-Methyl-A-nitrosourea, 0871 Methylnitrothiophene, 1844... 

Treatment of a nitrosourea with a base comprises the final step in a preparation of a diazomethane derivative. This has been successfully applied to the synthesis of trimethylsilyl diazomethane.243 244... 

Carmustine infusion solutions are administered over a period of one to two hours by slow infusion. The stability of carmustine, a nitrosourea derivative, after reconstitution and dilution depends on pH, temperature, radiation exposure, and sorption of delivery devices. Because of the pH factor, diluted solutions are more stable in 5% dextrose injection than in 0.9% sodium chloride injection. Different degradation mechanisms exist for the photoexposed and dark reactions. 

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