Synthesis and antitumor activity of cysteinyl-3,4-dihydroxyphenylalonines and related compounds

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Abstract
Structural analogs of 5-S-cysteinyl-3,4-dihydroxyphenylalanine (1), including several new compounds, were synthesized and tested for growth inhibition of cultured cells of human neuroblastoma YT-nu and Chinese hamster fibroblast Don-6. Some were also examined for antitumor activity against L1210 [mouse leukemia cells] and B-16 [mouse melanoma cells] in vivo. 4-S-Cysteinylcatechols and 2- and 4-S-cysteinylphenols, which cannot be prepared by conventional methods, were synthesized by the reaction of catechols and phenols with cystine in boiling aqueous HBr. 5-S-Cysteinyl- and 2-S-Cysteinyl-3,4-dihydroxyphenylalanine (1 and 2), L-dopa, and 2- and 4-S-cysteinylphenol (14 and 15) were toxic to the YT-nu cell line only, while 4-S-cysteinylcatechol (6), 3-S-cysteinyl-5-methylcatechol (8), 5-S-cysteaminyldopamine (9) and 4-methylcatechol were strongly toxic to both cell lines. Compounds 1 (1000 mg/kg), 6 (500 mg/kg), and 8 (400 mg/kg) increased the life span of L1210-bearing mice by 50, 50, and 43%, respectively, and compounds 1 and 8 were marginally effective against B-16 melanoma as well. Compound 9 was too toxic to show any activity. There was a good correlation between the cytotoxicity and the in vivo activity.

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