Structural analogs of L-glutamic acid .gamma.-(4-hydroxyanilide) and .gamma.-(3,4-dihydroxyanilide) as potential agents against melanoma

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Abstract
Nine heretofore unknown mono- and dihydroxyanilide analogs of the cytotoxic mushroom [Agaricus bisporus] metabolites L-glutamic acid .gamma.-(4-hydroxyanilide) (1) and L-glutamic acid .gamma.-(3,4-dihydroxyanilide) (3, agaridoxin) were synthesized and tested as inhibitors of the growth of B16 mouse melanoma cells in culture. The naturally occurring anilides 1 and 3 had ID50 [mean inhibitory dose] values of 0.10 and 0.27 mM, respectively. The analog of 1 in which the .gamma.-L-glutamyl moiety was replaced by .beta.-L-aspartyl showed only a 3-fold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a 10-fold decrease. Other structural modifications, such as O-methylation or deletion of the carboxyl or amino group in the side chain, led to compounds of still lower activity (ID50 > 1.0 mM). The only analog in the series with more activity than either 1 or 3 against B16 cells was L-glutamic acid .gamma.-(2,5-dihydroxyanilide) (14), which had an ID50 value of 0.051 mM. These data suggest that the .gamma.-L-glutamyl side chain in 1 or 3 plays a significant role in the biological action of these compounds, though some flexibility appears to exist insofar as the positioning of OH groups on the aromatic ring is concerned.