Structure-based design of nitrosoureas containing tyrosine derivatives as potential antimelanoma agents.
Two new nitrosoureas (TNUs), containing tyrosine derivatives as carriers of nitrosourea cytotoxic group have been synthesised. The physicochemical properties such as half-life time (tau(0.5)), alkylating and carbamoylating activities were determined. The nitrosoureas showed a higher inhibiting effect on the DOPA-oxidase activity of mushroom tyrosinase than that of the antitumour drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). In vitro cytotoxic effects of newly synthesised tyrosine containing nitrosoureas have been studied and compared to those of CCNU. A higher cytotoxicity to B16 melanoma cells than to YAC-1 and to lymphocytes was demonstrated for the tyrosine containing nitrosoureas in comparison with CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea derivatives as potential antimelanomic drugs might be developed.
Gadjeva
Vesselina
V
Department of Chemistry and Biochemistry, Medical Faculty, Thracian University, 11 Armeiska Street, BG-6000 Stara Zagora, Bulgaria. vgadjeva@mf.uni-sz.bg
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008546:Melanoma, Experimental; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002219:Carbamates; D009607:Nitrosourea Compounds; D014443:Tyrosine; D014442:Monophenol Monooxygenase; C070766:carbamic acid