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Carbamoylation reactions of N-methyl-N'-aryl-N-nitrosoureas and corresponding phenyl isocyanates to 5'-amino-5'-deoxythymidine: importance of carbamoylation in mouse skin carcinogenic processes.

Abstract
Carbamoylation reactions of N-methyl-N'-aryl-N-nitrosoureas (I-X: X = -OCH3, -CH3, -H, -Cl, and -COCH3) and of their corresponding phenyl isocyanates (II-X: X = -OCH3, -CH3, -H, -Cl and -COCH3) to the amino group of 5'-amino-5'-deoxythymidine have been kinetically studied in a PBS. The pseudo-first-order rate constants (kc x 10(4) s-1, 37 degrees C) are 9.21 for I-OCH3, 5.11 for I-CH3, 20.1 for I-H, 3.45 for I-Cl and 5.75 for I-COCH3. These rate constants correlated well with the tumorigenic potency of I-X to mouse skin (r = 0.761), but did not correlate with the other factors [solvolytic reactivity, alkylating activity to 4-(p-nitrobenzyl)pyridine, and mutagenicity on Salmonella typhimurium TA1535]. When the rate ratio (kc/ks) of the carbamoylation (kc) with the solvolysis (ks) was compared with the tumorigenic potency, a much better correlation was found between them (r = 0.876). Since II-X were too reactive to measure their kinetic data, the extent of their reactions at the 60 min time point was compared with the reactions of I-X. The reactivity of II-X (II-OCH3 greater than II-CH3 greater than II-H greater than II-Cl greater than II-COCH3) did not correlate with that of I-X (I-H greater than I-OCH3 greater than I-CH3 greater than I-Cl greater than I-COCH3), but both I-X and II-X gave the same carbamoylated and solvolysis products. The present results suggest that carbamoylation of amino groups in cellular constituents by N-nitrosoureas is a critical factor in inducing mouse skin tumors by the agents and that the generated isocyanates may not be the key intermediates for the carbamoylation reactions.
AuthorsK Yano
JournalCarcinogenesis (Carcinogenesis) Vol. 13 Issue 4 Pg. 699-702 (Apr 1992) ISSN: 0143-3334 [Print] England
PMID1576720 (Publication Type: Journal Article)
Chemical References
  • Cyanates
  • Dideoxynucleosides
  • Isocyanates
  • Nitrosourea Compounds
  • phenyl isocyanate
  • 5'-amino-5'-deoxythymidine
Topics
  • Animals
  • Cyanates (metabolism)
  • Dideoxynucleosides (metabolism)
  • Isocyanates
  • Mice
  • Nitrosourea Compounds (metabolism, toxicity)
  • Skin Neoplasms (chemically induced)
  • Structure-Activity Relationship

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