PubMed Health⌕ Search

Biomedical subjects

A B Foster

Publications and source records attributed to A B Foster.

At least 37 records · Page 2Linked to original sources
PubMed1980

Structure and reactivity of nitrosocimetidine.

The major product of reaction of cimetidine in 2 M hydrochloric acid in the prescence of excess sodium nitrite is a mono-nitroso derivative, the structure of which has been determined by the application of field desorption mass and proton magnetic resonance spectrometry. The methylating ability of nitrosocimetidine in phosphate buffer at pH 7 towards 3,4-dichlorobenzenethiol is comparable to that of the known gastric carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine.

Carcinogens↗
PubMed1980

Fluorinated analogues of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea: an attempt to control metabolism.

In seeking to block and thereby determine the role of the rapid in vivo hydroxylation of the cyclohexyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in relation to antitumor activity and tissue distribution, the 3-(1H-decafluorocyclohexyl) analogue (FCCNU) was synthesized. FCCNU showed marked toxicity and little activity against the intracerebral L1210 leukemia in mice. At pH 7 in phosphate buffer at room temperature FCCNU rapidly decomposed to give 1-(1H-decafluorocyclohexyl)-3-nitrosoimidazolidin-2-one (3) and thence, by loss of HF, the 1-(nonafluorocyclohexenyl) derivative (4); CCNU did not follow this decomposition pathway to any significant extent. Both 3 and 4 were unstable in the buffer, but each was isolated crystalline and characterized. The formation of 3 and 4 account for the biological properties of FCCNU.

Animals↗
PubMed1979

The metabolism of deuterated analogues of chlorambucil by the rat.

The antitumour agent chlorambucil (4[4-bis(2-chloroethyl)aminophenyl]-butyric acid) is converted by beta-oxidation in vivo into phenylacetic mustard (2[4-bis(2-chloroethyl)aminophenyl]acetic acid). This process may be disadvantageous from a therapeutic viewpoint since the metabolite has half the therapeutic index of the parent drug against the Walker 256 carcinoma in rats. In seeking to retard beta-oxidation, selectively deuterated analogues have been synthesised and administered to rats. Plasma levels of phenylacetic mustard after giving chlorambucil-beta-d2 were lower than those given by unlabelled drug, but the therapeutic activity was not significantly altered by deuteration. A dehydro derivative of chlorambucil was detected as an intermediate in the beta-oxidation pathway. The isotopic compositions of this metabolite, and of recovered chlorambucil, were measured in plasma samples taken after giving labelled chlorambucil (alpha-d2 and beta-d2 variants) to rats. Deuterium was almost totally lost from the alpha-d2 form and from its metabolite after 30 min and partially lost in 10 min. The beta-d2 variant and its dehydro-derivative retained the label. Possible mechanisms for deuteration loss are discussed. The design of novel analogues, based on these metabolic studies, is proposed.

Animals↗
PubMed1977

Myocardial uptake (rabbit) of six 99mTc-tagged pharmaceuticals and 85Sr after vasopressin-induced necrosis.

A new rapid method for producing myocardial necrosis in rabbits was developed, using percutaneous intramyocardial injection of vasopressin in peanut oil. The 15-min procedure resulted in a mortality rate of 15% and a success rate among surviving animals of 50%. When the lesions were 24 hr old, strontium-85 and a technetium-99m-tagged agent were injected intravenously simultaneously, and the animals were killed 1,6, and 24 hr later for tissue radioassay. Strontium-85 failed to accumulate appreciably in the lesions. Three bone-seeking technetium complexes (pyrophosphate, methylene diphosphonate, and imidodiphosphonate) produced lesion-to-normal myocardial ratios of 6,5, and 14, respectively, at 1 hr, and 20,30, and 33 at 6 hr. The ratios for 99mTc-glucoheptonate were only 2 at 1 hr and 4 at 6 hr, while the ratios of 99mTc-acetylcysteine and 99mTc-citrate were even lower.

Animals↗
PubMed1976

The use of deuterated analogs in qualitative and quantitative investigations of the metabolism of cyclophosphamide (NSC-26271).

Ring-deuterated analogs of cyclophosphamide (CP) (4-d2, 5-d, 4,6-d4, and 4,5,6-d6 derivatives) have been used to study the influence of deuterium substitution on the rates of metabolic pathways involving oxidation at C-4, and on the rate of elimination of acrolein from aldophosphamide. The magnitude of the deuterium isotope effect (kH/kD) associated with appropriate C-deuteration has been related to antitumor activity against the ADJ/PC6 murine plasma cell tumor. Isotope effects of 2.2 and 1.8 respectively, for the formation of 4-ketocyclophosphamide (4-keto-CP) and carboxyphosphamide, caused little or no change in antitumor activity (4-d2 and 4,6-d4 analogs compared with CP), but an isotope effect of about 5.3 for the beta-elimination pathway, consequent on 5,5-dideuteration, was paralleled by a marked drop in potency (7-13-fold increase in ED90) of 5,5-dideuterated analogs compared with that of CP. Analogs tetradeuterated in the bis(2-chloroethyl)amino function were used to quantitate CP and 4-keto-CP in human plasma and urine using stable-isotope dilution and direct-insertion electron impact mass spectrometry. The negative optical rotation of CP recovered from human urine after administration of the racemlc drug gave evidence for stereoselectivity in the metabolism.

Acrolein↗
PubMed1975

The quantitation of cyclophosphamide in human blood and urine by mass spectrometry-stable isotope dilution.

The levels of cyclophosphamide in the blood and the urine of patients have been monitored by direct insertion, electron impact mass spectrometry using the principle of stable isotope dilution. When a tetradeuterated analogue of the drug was added to a sample of blood or urine the concentration of cyclophosphamide could be determined from the ratio of the intensities of the signals (M-CH2 C1) characteristic for cyclophosphamide and the tetradeuterated analogue present in the mass spectrum of a chloroform extract. The procedure is highly specific for cyclophosphamide and obviates the need to use radioactively labelled cyclophosphamide for quantitation of the drug in man.

Carcinoma, Small Cell↗
PubMed1973

The alkylation of 2'-deoxyguanosine and of thymidine with diazoalkanes. Some observations on o-alkylation.

The reaction in ether-methanol between 2'-deoxyguanosine and diazomethane or its ethyl or n-butyl homologue gives 1-, O(6)- and 7-alkyl-2'-deoxyguanosine. N(2),O(6)-Dimethyl-2'-deoxyguanosine was also detected. The hydrolysis of the methyl and the ethyl derivatives gives the corresponding alkylguanines: the O(6)-alkyl-2'-deoxyguanosines were sequentially hydrolysed, first to 2-amino-6-alkoxypurines, subsequently to guanine. The mass spectra of O(6)-alkyl-2'-deoxyguanosines (methyl and ethyl) and of the corresponding 2-amino-6-alkoxypurines were determined. The reaction of diazomethane with thymidine afforded O(4)-methylthymidine, in addition to the previously detected 3-methylthymidine.

Alkylation↗