title: Synthesis and cytotoxic properties of new N-substituted 4-aminophenol derivatives with a potential as antimelanoma agents.
abstract: New tyrosinase-targeted compounds based on structural variants of the prototype unit 4-aminophenol have been synthesized and screened for their potential as antitumour agents against malignant melanoma. Cytotoxicity assays showed that N-4-hydroxyphenylglycine (NHPG) and its alpha-methyl derivatives methylphenylglycine and dimethylphenylglycine exhibit significant antiproliferative effects on pigmented human melanoma cell lines (HBL), with inhibitory concentrations at 50% (IC50) around 80 micrograms/ml. A marked increase in cytotoxicity was observed with morpholine-containing 4-aminophenols, e.g. N-(2-morpholinoethyl)-4-aminophenol, which showed an IC50 of 20 micrograms/ml of HBL cells. Much more pronounced was the effect of the diacetoxy-derivative, DiAcMoAc, which showed an IC50 of 15 micrograms/ml on HBL cells and as low as 2 micrograms/ml on tyrosinase-containing, non-pigmented human melanoma cells (LND1), with a toxicity response of the same order of magnitude as that of melphalan. These results open interesting perspectives in the design of new targeted pro-drugs against malignant melanoma.
authors.affiliation: Department of Organic and Biological Chemistry, University of Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Mascagna
authors.forename: G
authors.initials: G
authors.lastname: Ghanem
authors.forename: R
authors.initials: R
authors.lastname: Morandini
authors.forename: M
authors.initials: M
authors.lastname: d'Ischia
authors.forename: G
authors.initials: G
authors.lastname: Misuraca
authors.forename: F
authors.initials: F
authors.lastname: Lejeune
authors.forename: G
authors.initials: G
authors.lastname: Prota
mesh_terms: D000627:Aminophenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000627:Aminophenols; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D014442:Monophenol Monooxygenase; C026729:4-aminophenol