POLYHYDROXYLATED PHENYLACRYLIC ACID-DERIVATIVES AS NEW ANTITUMOR AGENTS

Preliminary evidence indicates that antitumor agents containing the o-dihydroxybenzene moiety exhibit enhanced antitumor activity toward malignant cells of high oxidative potential, such as melanoma cells. Based on this consideration, 11 hydroxybenzene acrylic acid derivatives of differing redox potential were prepared as potential substrates for the melanoma specific enzyme tyrosinase, that might exhibit general antitumor activity and enhanced cytotoxicity toward melanoma cells. Five of these compounds [alpha-cyano-beta-(4-hydroxyphenyl)-, alpha-cyano-beta-(3,4-dihydroxyphenyl)-, and alpha-cyano-beta-(3,4,5-trihydroxyphenyl)acrylic acid (THPPA), and 3,4-dihydroxy- and 3,4,5-trihydroxybenzalcyanoacetamide] were found to be substrates for tyrosinase with k(m) values from 0.08 to 4.13 mM and V(max) values from 0.18 to 3.02. These data indicate that as the number of hydroxy groups increases, the rate of oxidation increases, and that cyanoamides were faster reacting than corresponding cyanoacids, with dicyanides the least reactive. In contrast, cyanoamides were less effective as substrates than cyanoacids. In vitro studies showed all but two compounds were active against L1210 (IC50 range 21-980-mu-M), SK-MEL-28 (IC50 range 54-950-mu-M), and SK-MEL-30-3 (IC50 range 54-190-mu-M). Only THPPA was active in vivo against L1210 and B-16 melanoma.