Nitrosoureas

Nitrosoureas are having both practical and theoretical interest. They are very highly lipid soluble antineoplastic compoimds first synthesized at Southern Research Institute, Birmingham. 

A few important members of this category are discussed below, namely Carmustine and Lomustine. 

Carmustine may be prepared by interacting 1,3-bis (2-chloroethyl) urea with sodium nitrite and formic acid. It is a low-melting white powder that undergoes decomposition at 27°C and hence it is supplied as a lypholized powder. 

As it possesses the potential to cross the blood-brain-barrier, carmustine is employed specifically for brain tumours and other tumours, for instance leukemias, which have metastasized to the brain. A combination of carmustine and prednisone is used for the treatment of multiple myeloma. As a secondary therapy it is frequently employed in conjunetion with other antineoplastic agents for lymphomas and Hodgkin s disease. 

It is prepared by the decomposition of 1,3 -bis (2-chlorethyl)-1 -nitrosourea in the presence of two equivalents of cyclohexylamine to yield an imsymmetrieal urea whieh on nitrosation with sodium nitrite and formie acid offers the desired eompoimd. 

Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU) generate alkyl car-bonium ions and isocyanate molecules and hence are able to interact with DNA and other macromolecules. These agents, which are lipid soluble, cross the blood-brain barrier and are therefore effective in treating brain tumors. They are bone marrow depressants. 

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Nitrosothiol Nitroso thioproline Nitrosoureas Nitrostat Nitrosyl chloride... 

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

Chloroethyl)-3-(4-methylcyclohexyl)-l-nitrosourea (Methyl-CCNU Semustine) [13909-09-6] (Suppl. 7 1987) Chromium [VI] compounds (Vol. 49 1990)... 

Chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) [13010-47-4] (Vol. 26, Suppl. 7 1 (NB Overall evaluation upgraded from 2B to 2A with supporting evidence from other carcinogenicity and its mechanisms)... 

Nelson and Scliut investigated the reaction of 5a-cholestanone (lb) with diazomethane in a search for a direct, one-step preparation of A-homo ketones. Using a large excess of diazomethane generated in situ from A-methyl-nitrosourea with potassium hydroxide in ether-methanol at 0°, 5a-cholestanone (lb) is converted into the 7-membered ring homolog (3b) as the predominant product. Both theoretically possible A-homo ketones can be expected with an unsymmetrically-substituted cyclohexanone such as 5a-cholestanone (lb). 

Reaction of metal hydride complexes with N-nitrosoamides, e.g. Af-methyl-7V-nitrosourea ... 

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. 

Alkylating Agents. Figure 3 Chemical structure of some nitrosoureas. 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

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

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. 

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. 

This far into a nitrosamine symposium it should hardly be necessary to point out that nitrosamines are technically just one of a group of Ji-nitroso compounds that also includes nitros-amides, nitrosocarbamates, nitrosoureas, etc. Or that nitrosa-table pesticides encompass all the categories just mentioned and more. Or that many diverse pesticides, including herbicides, insecticides, and fungicides have been converted to Ji-nitroso derivatives in the laboratory (a recent review contained a 3-page, probably incomplete, compilation), or that some of the Ji-nitroso compounds thus synthesized were determined to be carcinogenic in test animals or mutagenic in various assays. 

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. 

The GSH reductase inhibitor l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) also promotes corneal swelling in the isolated cornea. The addition of GSH prevents the action of BCNU as the cornea needs a constant supply of NADPH for maintaining adequate concentrations of reduced glutathione for the detoxification of hydrogen peroxide. It has been shown that hydrogen peroxide and BCNU primarily affect the permeability of the endothelial cells rather than the active processes transporting sodium and chloride ions across the membrane (Riley, 1985). 

BCF Basophil chemotactic factor B-CFC Basophil colony-forming cell BCG Bacillus Calmette-Guerin BCNU l,3-bis(2-chloroethyl)-l-nitrosourea bFGF Basic fibroblast growth fiictor Bg Birbeck granules BHR Bronchial hyperresponsiveness BHT Butylated hydroxyroluene b.i.d. Bis in die (twice a day)... 

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