title: 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.
authors.affiliation: Department of Chemistry, Saitama Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yano
mesh_terms: D000818:Animals; D003485:Cyanates / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000378:metabolism*; D017953:Isocyanates; D051379:Mice; D009607:Nitrosourea Compounds / Q000378:metabolism* / Q000633:toxicity; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship
chemical_list: D003485:Cyanates; D015224:Dideoxynucleosides; D017953:Isocyanates; D009607:Nitrosourea Compounds; C025319:phenyl isocyanate; C024082:5'-amino-5'-deoxythymidine