Nitrosourea Derivatives

Nitrosourea derivatives are alkylating agents that include a nitroso (R-NO) group and a urea. 

Babson, J. R., and Reed, D. J. Inactivation of glutathione reductase by 2-chloroethyl nitrosourea-derived isocyanates. Biochem. Biophys. Acta. 83 754-762,1978. 

Similarly for the reverse reaction of denitrosation of the nitrosourea derivative, the general rate equation is given by (14) since, in the presence of the nitrous acid trap hydrazine sulphate, step (o) can be neglected. Again if -i[X-] ki no catalysis by X is predicted. The reversibility of the reaction was tested quantitatively by noting the variation of the observed rate constant... 

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. 

Some nitrosoamines have other biological effects than carcinogenic action. A/-(2-Chloroethyl)-A -cyclohexyl-A/-nitrosourea (4.15) has a cytostatic effect (Ferguson, 1975) and another A/-nitrosourea derivative, streptozotocin (4.16), is an antibiotic (Herr et al., 1967). 

Activity E. inhibits the mutagenicity of benzpyrene and other aromatic hydrocarbons, as well as ahatox-ins, nitropyrene, and nitrosourea derivatives. E. and E.-derivatives inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid... 

Streptozotocin, a broad spectrum antibiotic with anitumour activity produced by Streptomyces achromogenes [163], has been shown to be the A -methyl-A -nitrosourea derivative of glucosamine (XLa) by chemical degradation and spectroscopic studies [164], Two syntheses have confirmed the structure, one of which is suitable for the commercial preparation of the drug [165]. Treatment of glucosamine with 7V-methylisocyanate has afforded the A -methylurea derivative (XLb), which gave streptozotocin on treatment with nitrogen trioxide. 

Treatment of per-O-acetylated glycosylamines with 2-chloroethyl isocyanate, followed by nitrosation (sodium nitrite in formic acid) and deacetylation, yielded a series of (2-chloroethyl)nitrosourea derivatives [e.g. l-(2-chloroethyl)-3-(j3-D-gIucopyranosyl)-l-nitrosourea (150)], which showed remarkable anti-... 

Table 8. Comparison of the ECso values of several 3 -amino analogues of pyrimidine deoxyribonucleosides and their corresponding nitrosourea derivatives on the replication of L1210 cells in vitro.

Epoxide Opening. - Ring-opening of epoxide 14 by azide was used in a new synthesis of methyl 3-aniino-3,4-dideoxy-P-D-j(y/o-hexopyranoside 17 (Scheme 4), which was required for the preparation of nitrosourea derivatives. Intermediate azides 15 and 16 were obtained in a 3 2 ratio. An alternative route to epoxide 14 was also reported. The D-r/bo-aziridine 19 was obtained from the D-lyxo-epoxide 18 (Scheme S) and used in the synthesis of epimino-nucleoside analogues (see Chapter 20). Syntheses of methyl 2,3-rra/u-aminofluoropentofuranosides from 2,3-cpoxides is covered in Chapter g. 

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