Journal of medicinal chemistry

Structural analogues of L-glutamic Acid gamma-(4-hydroxyanilide) and gamma-(3,4-dihydroxyanilde) as potential agents against melanoma.

PMID 490547


Nine heretofore unknown mono- and dihydroxyanilide analogues of the cytotoxic mushroom 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 values of 0.10 and 0.27 mM, respectively. The analogue of 1 in which the gamma-L-glutamyl moiety was replaced by beta-L-aspartyl showed only a threefold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a tenfold 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 greater than 1.0 mM). The only analogue 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.

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3,4-(Methylenedioxy)aniline, 97%