In the search for new anticancer drugs. XXV: Role of N-nitrosated Amadori compounds derived from glucose-amino acid conjugates in cancer promotion or inhibition

Article abstract of DOI:10.1002/jps.2600820621

Earlier investigators found that some N-nitrosated Amadori compounds, derived from glucose and amino acid condensation reactions, exhibit mutagenic properties and theorized that these potentially carcinogenic compounds might be formed in the human digestive system. To further investigate these compounds, N-nitrosated Amadori compounds [i.e., N-(1-deoxy-D-fructos-1-yl)- L-N-nitroso-glycine (5a), -threonine (5b), -methionine (5c), -valine (5d), - phenylalanine (5e), and -tryptophan (5f)] were synthesized by modifications of known methods. Acute toxicity tests of 5a, 5b, 5c, 5d, 5e, and 5f in male Swiss mice produced the following lowest lethal limits of toxicity: 2000, 2000, 4000, 3000, 2000, and 6000 mg/kg, respectively, whereas the highest tolerated doses were 1750, 1500, 3000, 1500, and 5000 mg/kg, respectively. The 50% lethal dose (intraperitoneally) for 5b in mice was ~1777 mg/kg. This value is at least three times higher than that for the over-the-counter drug Ibuprofen (i.e., 495 mg/kg, intraperitoneally, in mice). Compounds 5b, 5c, 5d, and 5f were evaluated in vitro by the National Cancer Institute primary antitumor screen consisting of 60 cell lines. None of the four compounds caused a significant inhibition of cell growth, even at the maximum dosage of 10^-4 M. Compounds 5a-f were tested in vivo against the lymphocytic leukemia P388, and 5b and 5f were tested against the lymphoid leukemia L1210 in CDF₁ male mice following the National Cancer Institute protocol. There were no significant differences in results between the control and drug-treated mice. The percent increase in lifespan ranged from -15 to +15 (T/C = 85-115) for P388 and from -5 to +1 (T/C = 95-101) for L1210, whereas the values for the positive control 5-fluorouracil were 71 and 67 (T/C = 171 and 167), respectively. The combination of very low acute toxicity, low in vitro cytotoxicity in primary tumor screens, and no activity in vivo led to the hypothesis that none of the compounds 5a-f are carcinogenic or cytotoxic. It is possible that these compounds are not metabolically activated by either α- or β-oxidations or by retro-aldol cleavage reactions.