IN THE SEARCH FOR NEW ANTICANCER DRUGS .25. ROLE OF N-NITROSATED AMADORI COMPOUNDS DERIVED FROM GLUCOSE-AMINO ACID CONJUGATES IN CANCER PROMOTION OR INHIBITION

Earlier investigators found that some N-nitrosated Amadori compounds, derived from glucose and amino acid condensation reactions, exhibit mu tagenic properties and theorized that these potentially carcinogenic c ompounds might be formed in the human digestive system. To further inv estigate these compounds, N-nitrosated Amadori compounds [i.e., N-(1-d eoxy-D-fructos-1-yl)-L-N-nitroso-glycine (5a), -threonine (5b), -methi onine (5c), -valine (5d), -phenylalanine (5e), and -tryptophan (5f)] w ere synthesized by modifications of known methods. Acute toxicity test s of 5a, 5b, 5c, 5d, Se, and 5f in male Swiss mice produced the follow ing lowest lethal limits of toxicity: 2000, 2000, 4000, 3000, 2000, an d 6000 mg/kg, respectively, whereas the highest tolerated doses were 1 750, 1500, 3000, 1500, and 5000 mg/kg, respectively. The 50% lethal do se (intraperitoneally) for 5b in mice was approximately 1777 mg/kg. Th is value is at least three times higher than that for the over-the-cou nter drug ibuprofen (i.e., 495 mg/kg, intraperitoneally, in mice). Com pounds 5b, Sc, 5d, and 5f were evaluated in vitro by the National Canc er Institute primary antitumor screen consisting of 60 cell lines. Non e 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 i n vivo against the lymphocytic leukemia P388, and 5b and 5f were teste d against the lymphoid leukemia L1210 in CDF1 male mice following the National Cancer Institute protocol. There were no significant differen ces 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 an d from -5 to +1 (T/C = 95-101) for L1210, whereas the values for the p ositive control 5-fluorouracil were 71 and 67 (T/C = 171 and 167), res pectively. The combination of very low acute toxicity, low in vitro cy totoxicity in primary tumor screens, and no activity in vivo led to th e hypothesis that none of the compounds 5a-f are carcinogenic or cytot oxic. It is possible that these compounds are not metabolically activa ted by either alpha- or beta-oxidations or by retro-aldol cleavage rea ctions.