Characterization of the cytotoxic activity of nitric oxide generating N-nitroso compounds.
The NO-generating abilities of aromatic N-nitroso compounds (nitrosoureas, nitrosamides and nitrosamines), and N-acetyl-S-nitroso-DL-penicillamine at ambient temperature were compared by employing the Griess reaction. 3,3-Dibenzyl-1-(4-tolyl)-1-nitrosourea showed the greatest NO-generating ability among the tested compounds. The NO-generating ability of the aromatic N-nitrosoureas and N-nitrosamides was greater than that of the N-nitrosamines, presumably reflecting differences in electrostatic repulsion between the carbonyl oxygen and nitroso oxygen in these compounds. In addition, a conjugative effect between the aromatic ring carbon and neighboring nitrogen influences the NO-generating ability; the conjugative effect in the case of N-nitrosoureas and N-nitrosamides having an ortho-alkyl substituted aromatic ring, or N-nitrosamines having a bulky N-group, such as tert-butyl, is decreased by an increase in steric hindrance around the nitroso group. The N-NO bond then becomes more stable. The NO-generating ability was related to the reciprocal of the ID50 value for growth inhibition of cultured L-5178 Y cells by the aromatic N-nitroso compounds. On the other hand, NO production from the aliphatic N-nitroso compounds was not observed under our conditions, and these N-nitroso compounds did not show effective cytotoxic activity.
Tanno
M
M
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
Sueyoshi
S
S
Miyata
N
N
Umehara
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009603:Nitroso Compounds; D009569:Nitric Oxide