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
G. Sosnovsky et al., 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, Journal of pharmaceutical sciences, 82(6), 1993, pp. 649-656
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.