Polyhydroxylated phenylacrylic acid derivatives as new anti-tumor 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 Km values from 0.08 to 4.13 mM and Vmax 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 microM), SK-MEL-28 (IC50 range 54-950 microM), and SK-MEL-30-3 (IC50 range 54-190 microM). Only THPPA was active in vivo against L1210 and B-16 melanoma.
Hussoin
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Laboratory of Molecular Dermatologic Oncology, Dana-Farber Cancer Institute, Boston, MA.
FitzGerald
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GB
Wick
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D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002396:Catechols / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004563:Electrochemistry; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000179:Acrylates; D000970:Antineoplastic Agents; D002396:Catechols; D014442:Monophenol Monooxygenase