N-Nitrosoureas

A solution of 5 mmol diazomethane, prepared from N-methyl-N-nitrosourea (0.62 g, 6 mmol), in 5 mL pentane is added to 1728 a (0.5 g, 5 mmol) [4] at 0°C and the reaction mixture warmed to room temperature. After 30 min the yellow color of CH2N2 has disappeared and the reaction mixture is evaporated. The residue is extracted with boiling pentane to give 0.66 g (93%) 3-tert-butyl-lH-l,2,4-di-azaphosphol, m.p. 74°C [30] (Scheme 11.10). 

Analysis of reaction mixtures for 1-propanol and 2-propanol following incubation of NDPA with various rat liver fractions in the presence of an NADPH-generating system is shown in Table I ( ). Presence of microsomes leads to production of both alcohols, but there was no propanol formed with either the soluble enzyme fraction or with microsomes incubated with SKF-525A (an inhibitor of cytochrome P450-dependent oxidations). The combined yield of propanols from 280 ymoles of NDPA was 6.1 ymoles and 28.5 ymoles for the microsomal pellet and the 9000 g supernatant respectively. The difference in the ratio of 1- to 2-propanol in the two rat liver fractions may be due to differences in the chemical composition of the reaction mixtures (2) Subsequent experiments have shown that these ratios are quite reproducible. For comparison, Table I also shows formation of propanols following base catalyzed decomposition of N-propyl-N-nitrosourea. As expected (10,11), both propanol isomers were formed, the total yield in this case being almost quantitative. 

OS 49] [R 17] [R 26] [P 36] At almost quantitative conversion, yields of 90% of two (in a first run) unidentified products and of 10% N,N -diethylurea were reported, accompanied by small amoimts of the mono-product [38], AH products no longer contained any C=S moiety, hence were somehow attacked via a nucleophilic route. By subsequent MS and IR analysis, the two main products were identified as N,N -diethyl-N-nitrosourea and, probably, N,N -diefhyl-N,N -dinitrosourea. By optimization of the [P 23] procedure, 100% selectivity for the nitration of N,N -diethylurea to N,N -diethylurea was achieved. 

Boileau, T. W., Z. Liao, S. Kim et al. 2003. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 95(21) 1578—1586. 

Carbamate esters of zinc, zineb, and ziram are carcinogenic and teratogenic in animals, but this is attributed to the action of the carbamate esters and not to zinc (Elinder 1986). Results of studies with small mammals showed zinc to be cocarcinogenic with 4-nitroquinoline-N-oxide on oral cancer, and with N-ethyl-N-nitrosourea on brain cancer (Leonard and Gerber 1989). 

Although N-methyl-N-nitrosourea can induce cancer in human beings, its derivatives were found to be potent antitumor agents. l,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and l-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-l-nitrosourea (PCNU) l-(2-Choroethyl)-3-(4-methylcyclo-hexyl)-l-nitrosourea and l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea showed antitumor activity by alkylating with DNA [82-84]. N-Nitrosourea-based prodrugs designed to become activated by tumor-associated proteases were found to provide enhanced... 

Connell, J.R. and Medcalf, A.S. (1982). The induction of SCE and chromosomal aberrations with relation to specific base methylation of DNA in Chinese hamster cells by N-methyl-n-nitrosourea and dimethyl sulphate. Carcinogenesis 3 385-390. 

Antioxidant activity. Asafetida, administered orally to Sprague-Dawley rats at doses of 1.25% and 2.5% w/w, significantly restored the level of antioxidant system, depleted by N-methyl-N-nitrosourea treatment. There was a significant inhibition in lipid peroxidation as measured by thiobar-bituric acid-reactive substances in the liver of rats . 

Chemomodulatory influence. Asafetida, administered orally to Sprague-Dawley rats at doses of 1.25% and 2.5% w/w in diet, produced an increase in the development and differentiation of ducts/ductules and lobules and a decrease in terminal end buds as compared to both normal and N-methyl-N-nitrosourea-treated control animals. Asafetida treatment significantly reduced the levels of cytochrome P450 and b5. There was an enhancement in the activities of glutathione-S-transferase, deoxythymi-dine-diaphorase, superoxide desmutase, catalase, and reduced glutathione " " . Central nervous (CNS) effects. Ethanol extract of the dried gum, administered orally to adults at a dose of 20 mL/person, was active "" . 

Pathway of Methyl propionate Formation from the Alkaline Degradation of N-Propionyl-N-nitrosourea proposed by Kirmse (28)... 

The Druckrey-Preussmann review, however, contains reasonably quantitative data for a variety of molecular types including N-nitrosoureas, and cyclic and acyclic N-nitrosodialkylamines. 

RoscOE, J.P. and Claisse, P.J. (1978). Analysis of N-ethyl-N-nitrosourea induced brain carcinogenesis by sequential culturing during the latent pe iod. I. Morphology and tumorigenicity of the cultured ceUs and their growth in agar, J. NatL Cancer Inst. 61,381. 

Thielmann, H.W., Schroder, C.H., O Neill, J.P., Brimer, P.A., and Hsie, A.W. (1979). Relationship between DNA alkylation and specific-locus mutation induced by N-methyl- and N-ethyl-N-nitrosourea in cultured Chinese hamster ovary cells (CHO/HGPRT system), Chem. BioL Interact 26,233. 

N-Ethyl-N-nitrosourea is one of the most potent carcinogens known.773 774 These compounds, as well as diazomethane and other related substances, probably act via a common intermediate CH3N2+ or C2H5N2+.775... 

Colon Inhibition of N-methyl-N -nitrosourea (MNU) induced colon tumors [44]... 

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