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

Abstract

A number of congeners of the antitumor compound L-canaline, [l-2-amino-4-(aminooxy)butyric acid], a structural analog of L-ornithine, have been synthesized 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-canaline congeners in which the carbon chain length has been increased by one methylene unit exhibit a significant loss in cytotoxicity relative to the parent compound. Congeners in which the carbon chain length is decreased by one methylene unit retain the cytotoxicity of the parent compound against cultured MIA-PaCa-2 cells. Loss of the aminooxy or α-amino group of L-canaline severely curtails cell growth-inhibitory activity. With the exception of the n-octyl ester, esterification of L-canaline with simple alcohols has little effect on overall growth-inhibiting activity. It is noteworthy that the unnatural D-enantiomer of canaline is as deleterious to MIA-PaCa-2 cell growth as the naturally occurring L-enantiomer. Drug Dev. Res. 47:170–177, 1999. © 1999 Wiley-Liss, Inc.