Synthesis and structure-activity studies of some antitumor congeners of L-canaline

A number of congeners of the antitumor compound L-canaline, [L-2-amino-4-(a minooxy)butyric acid], a structural analog of L-ornithine, have been synthe sized and their growth-inhibitory effects evaluated in cultured MIA-PaCa-2 cells, a human pancreatic adenosarcoma, by the 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide assay. The results indicate that L-canalin e congeners in which the carbon chain length has been increased by one meth ylene unit exhibit a significant loss in cytotoxicity relative to the paren t compound. Congeners in which the carbon chain length is decreased by one methylene unit retain the cytotoxicity of the parent compound against cultu red MIA-PaCa-2 cells. Loss of the aminooxy or alpha-amino group of L-canali ne severely curtails cell growth-inhibitory activity. With the exception of the n-octyl ester, esterification of L-canaline with simple alcohols has l ittle effect on overall growth-inhibiting activity It is noteworthy that th e unnatural D-enantiomer of canaline is as deleterious to MIA-PaCa-2 cell g rowth as the naturally occurring L-enantiomer. (C) 1999 Wiley-Liss, Inc.