N-nitroso-N-butylurea (I) gave urea, an acidic substance from the butyl group of (I), butylurea, and N-(3-hydroxybutyl)urea from urine within 24 hr as (I) metabolites. The (I) carbamoyl group bound to proteins but not nucleic acids.
IDENTIFICATION AND USE: N-Nitroso-N-butylurea (BNU) is not produced commercially in the USA. HUMAN STUDIES: There are no data available. ANIMAL STUDIES: The increased incidence of neoplasms in rats and mice fed butylurea and sodium nitrite in combination may result from in vivo formation of the carcinogen BNU. Considerable number of ovarian tumors were produced in adult rats treated with multiple oral or im administration of BNU. Cases of ameloblastic odontomas were found in rats treated with multiple oral administration of BNU. BNU, a strong leukemogen for rats and mice, was administered prenatally, neonatally, and to sucklings via maternal milk in the rats. Contrary to expectations, leukemia developed in only one rat of all the offspring of the mother animals that received the BNU treatment during their pregnancy. BNU was injected once at dosage levels of 150 or 75 mg/kg into 3- or 6-week-old male mice. Intestinal tumors occurred in 100% of the mice that survived more than 15 weeks after injection with a high dose of BNU at 6 weeks of age, and in 35 to 70% of the mice in other treatment groups. T-cell leukemias have been induced in adult mice by 12 or 15 weeks of exposure to BNU in the drinking water. Repeated BNU (5 mg/day, orally) administration to rats caused atrophies of thymus, lymph nodes and spleen at early stage of treatment. O6-Butylguanine was detected in the urine of rats given the butylating agent BNU. This suggests that O6-butylguanine formation in nucleic acids might be repaired in vivo, possibly by base excision, besides other mechanisms.
Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further treated with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues.
No female rats treated with a small amount of N-nitrosobutlyurea (NBU) developed mammary tumors, multiple mammary tumors developed if adminstration of a small amount of NBU was followed by a prolonged treatment of either diethylstilbesterol or 17-beta-estradiol.
Effects of barbital (BB) on neuro-oncogenesis were examined in a rat transplacental carcinogenesis model. Pregnant F344 rats were divided into 7 groups. Dams in group I received subcutaneous injections of 10 mg/rat 1-butyl-1-nitrosourea (BNU) on the days 15, 18 and 21 of pregnancy and dams in groups II-IV, 1 mg/rat 1-butyl-1-nitrosourea on the same time schedule. In addition to the treatment with 1-butyl-1-nitrosourea, dams in group IV were given 0.125% barbital solution as their drinking water from the day 12 of pregnancy to parturition. Offspring in groups III and IV received 0.125% barbital solution as drinking water from 4 weeks of age until the termination of the study. Animals in groups V and VI were given 0.25% and 0.125% barbital solutions, respectively, in the peri- and postnatal period without 1-butyl-1-nitrosourea treatment. Dams in group VII received 250 mg/kg barbital subcutaneously on the days 15, 18 and 21 of pregnancy. Offspring in all groups were observed until 105-116 weeks of age. High yields of neurogenic tumors, such as gliomas and neurinomas, were observed in group I. In groups II, III and IV, single cases of a chordoma, a granular cell tumor, and a neurinoma and a malignant reticulosis, which are known to occur spontaneously, were noted, although no gliomas were found. No neurogenic tumors were observed in groups V-VII. With regard to lesions other than those in neurogenic organs, a significant increase in liver tumors was observed in group III compared to group II. In contrast, lung tumors were not found in group III, while they were observed in groups II and IV. These results suggest that BB has no neuro-carcinogenic activity in the rat transplacental carcinogenesis model.
The enhancing effects of o-vanillin ... on structural chromosome aberrations induced by alkylating agents were studied in cultured Chinese hamster cells. o-Vanillin was not a clastogen by itself. When cells were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the presence of 400 ug/mL of o-vanillin for 2 hr, the frequency of aberrant cells with chromosome aberrations was increased 2.8-fold compared with cells treated with N-methyl-N'-nitro-N-nitrosoguanidine alone. The total number of breakage-type and exchange-type aberrations was increased 18.5- and 8.3-fold, respectively. The enhancing effects were also observed for chromosome aberrations induced by N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. On the other hand, those induced by N-butyl-N-nitrosourea were only slightly enhanced. ...
Substituted diazoalkanes react smoothly, in the presence of catalytic amounts of Pd(OAc)(2), with a range of vinyl- and dienylboronates, affording in good to excellent yields, the corresponding trisubstituted cyclopropanes. The reaction is remarkably regio-, chemo-, and diastereoselective. The synthetic utility of this novel protocol is illustrated by the efficient assembly of the middle fragment of ambruticin.
The nitrosation ofN-alkylureas: Evidence for a proton transfer mechanism
The kinetics of the nitrosation of methyl, ethyl, propyl, butyl, and allyl urea were studied by conventional and stopped-flow spectrophotometry in the presence or absence of acetate or mono-, di-, or trichloroacetate anions. In the presence of a large excess of urea, the observed rate equation wasv = [urea][nitrite][H+](2)/K-a + [H+](theta + xi K-R[carboxylic acid]/K-R + [H+])where K-a is the acidity constant of nitrous acid and K-R that of the carboxylic acid. The ureas exhibited the reactivity order methylurea much greater than (ethylurea approximate to propylurea approximate to butylurea) much greater than allylurea. Experiments in D2O afforded values of k(H2O)/kD(2)O in general agreement with the values 4.1-5.5 predicted by a semiclassical transition state theory of kinetic isotope effects [i.e., kH(2)O/kD(2)O = exp(0.130h<(nu)over bar>/kT)], where <(nu)over bar> is the frequency of[GRAPHICS]stretching (2700-2250 cm(-1)) in the protonated urea. This result, the observed catalysis by carboxylate ions and the value of the Bronsted parameter beta(0.45) show the rate-controlling step of these reactions to be the transfer of a proton from the protonated N-alkyl-N-nitrosourea to the solvent or to the organic anion, if present. The observed order of substrate reactivities is explicable in terms of the capacity of the protonated N-alkyl-N-nitrosourea for forming a hydrogen bond with the water molecule to which the proton will be transferred, and the degree to which the formation of such bonds is hindered by the hydrophobic alkyl chain of the nitrosourea. (C) 1996 John Wiley & Sons, Inc.
