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Urefhane, N-hydroxyurefhane, hydrazine and sume related compounds were tested in C57BL/6 and S W R mice for activity as lung carcinogens, promoters of X-ray leukaemogenesis, and skin tumour initiators. Equimolar doses were used where possible. N-hydroxyurethane (ethyl hydroxycarbamate) was as strongly coleukaemogenic as urethane, and equally or less active than urethane as a lung carcinogen. Methyl and n-propyl hydroxycarbamates were inactive in all three tests, which suggests that the chemical specificity of urethane is not due to an ethyl-specific N-hydroxylating system. Acetylurethane showed considerable lung-carcinogenic and coleukaemogenic activities, and N-methoxyurethane (ethyl methoxycarbamate) and n-propyl carbamate showed weak lung-carcinogenic activities. Earlier reports that hydroxyurea is not a lung carcinogen were confirmed, but a weak coleukaemogenic effect war apparent. Hydrazine sulphate showed a weak but definite activity as lung carcinogen despite the low dose used, and on a molar basis appeared to be almost as active a s urethane. Methylhydrazine sulphate was inactive.The effects of single injections on the thymus weight of C57BL/6 mice were compared for four of the test compounds. N-hydroxyurethane produced an earlier and stronger depression of thymus weight than urethane, n-propyl hydroxycarhamate showed a definite but short-lived effect, and n-propyl carbamate was almost inactive. The results suggest that hydroxycarbainates exert a direct action on thymus weight, in addition to an action via conversion into the corresponding carbamates.
Urefhane, N-hydroxyurefhane, hydrazine and sume related compounds were tested in C57BL/6 and S W R mice for activity as lung carcinogens, promoters of X-ray leukaemogenesis, and skin tumour initiators. Equimolar doses were used where possible. N-hydroxyurethane (ethyl hydroxycarbamate) was as strongly coleukaemogenic as urethane, and equally or less active than urethane as a lung carcinogen. Methyl and n-propyl hydroxycarbamates were inactive in all three tests, which suggests that the chemical specificity of urethane is not due to an ethyl-specific N-hydroxylating system. Acetylurethane showed considerable lung-carcinogenic and coleukaemogenic activities, and N-methoxyurethane (ethyl methoxycarbamate) and n-propyl carbamate showed weak lung-carcinogenic activities. Earlier reports that hydroxyurea is not a lung carcinogen were confirmed, but a weak coleukaemogenic effect war apparent. Hydrazine sulphate showed a weak but definite activity as lung carcinogen despite the low dose used, and on a molar basis appeared to be almost as active a s urethane. Methylhydrazine sulphate was inactive.The effects of single injections on the thymus weight of C57BL/6 mice were compared for four of the test compounds. N-hydroxyurethane produced an earlier and stronger depression of thymus weight than urethane, n-propyl hydroxycarhamate showed a definite but short-lived effect, and n-propyl carbamate was almost inactive. The results suggest that hydroxycarbainates exert a direct action on thymus weight, in addition to an action via conversion into the corresponding carbamates.
The adenosine analog 9-0-D -ribofuranosyl-6-hydroxylaminopurine (2) (HAPII) was found to possess marked antileukemic activity in mice (3) and inhibited the growth of Streptococcus fueculis (3c). Pharmacological studies of rats and dogs revealed that treatment with HAPR induced methemoglobinemia (4), a toxic manifestation also uncovered in clinical trials (5). Since hydrolysis of HAPK by ox heart adenosine deaminase to inosine occurs (6), it is likely that the liberation of hydroxylamine may be the cause of the hematoxicity noted above, although this requires confirmatory study (7). It is worth mentioning that prolonged administration of hydroxylamine to mice produced anemia and splenomegaly, and complete inhibition of spontaneous mammary tumors (8). However, hydroxylamine was ineffective against transplanted mouse tumors and leukemias (9). The preparation of 7-deaza-HAPK, an analog of 7-deazaadenine which is n o t affected by enzymatic deamination, has been reported (10).'The synthesis of 9-0-D-arabinofuranosyl-6-hydroxylaminopurine was undertaken to study its possible growth inhibitory activity and behavior towards adenosine deaminase. It is well known t h a t derivatives with antitumor activity have been obtained by replacement of the ribosyl moiety of adenosine (1 1) or cytidine (12) by arabinosyl. ' r he synthesis of 9 -/3-Darabinofuranosyl-6-hy drox ylaminopurine (2) was achieved in 78% yield when 9-p-Darabinofuranosyl-6-chloropurine (1) (13) was stirred with an excess of 0.6 M ethanolic hydroxylamine at 25" for 5 days. The usual method (14) for the preparation of a variety of hydroxylaminopurines and their ribosyl derivatives, namely refluxing of the appropriate chloro or methylmercapto compound with ethanolic hydroxylamine with or without chIoride ions (14b), when applied to 1 gave a syrupy material from which compound 2 could n o t be isolated (15). Attempts to prepare 2 by reaction of 9-P-D-arabinofuranosyl-6mercaptopurine or its 6-methyl derivative (13) with ethanolic hydroxylamine in the presence of chloride ions led to a poor yield of 2. Compound 2 was readily reduced to 9-~-D-arabinofuranosyladenine (3) (13) with Kaney nickel. Preliminary in uitro tests carried o u t by Dr. W. Kreis indicate that compound 2 is not a substrate for adenosine deaminase. 1 2 3 SCHEME 1 EXPERIMENTAL (16) -p-~-Arabinofuranosyl-6-hydroxylaminopurine (2).A suspension of 9 -p-D-arabinofuranosyI-6ehloropurine (13) (1, 3.40 g., 5.1 mmole) i : 0.6 M ethanolic hydroxylamine (14a) (450 ml.) was stirred at 25 . The solid dissolved after severa1 hours and later a copious precipitate appeared. Stirring was continued for a total of 5 days. The precipitate was filtered and washed with ethanol, suspended and stirred in cold water (40 ml.) andocollected to yield 2.65 g. (78%) of white microneedles, m.p. 204 dec. An analytical sample was prepared by washing with cold water and ethanol, m.p. 206" dec, [a] ' 0' +6" ( c 0.5, water).Compound 2 gave positive ferric chloride and phosphomolybdate tests, indicative of the hydroxylamino function; ...
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