ABSTRACT
Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.
Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Monophenol Monooxygenase/metabolism , Prodrugs/therapeutic use , Antineoplastic Agents/pharmacokinetics , Humans , Melanins/biosynthesis , Melanins/physiology , Melanoma/etiology , Melanoma/metabolism , Prodrugs/pharmacokineticsABSTRACT
Boron-containing complexes that have the potential to irreversibly accumulate in melanoma cells have been prepared by reaction of amino acids with 9-methoxy-9-borabicyclo[3.3.1]nonane. The ability of each complex to act as a substrate for tyrosinase has been probed by oximetry. Increased uptake of the lead candidate in a tyrosinase-rich cell line, compared with a tyrosinase-absent cell line, is reported, with results correlating well with that for a drug currently approved for BNCT.
Subject(s)
Boron Compounds/chemical synthesis , Boron Compounds/pharmacology , Melanoma/drug therapy , Melanoma/pathology , Boron Compounds/chemistry , Boron Compounds/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Humans , Molecular Structure , Oxidation-Reduction/drug effects , Structure-Activity RelationshipABSTRACT
The addition of isocyanides to pyridinium salts is studied. The process takes place efficiently when a carboxamido group is present in the 3 position of the pyridine ring. The outcome of the reaction involves the stabilization of the nitrilium intermediate by the amide, which suffers a mild dehydration, leading regioselectively to beta-cyano-gamma-carbamoyl-1,4-dihydropyridines. In this way, a variety of nicotinamide derivatives were carbamoylated. Extension to quinolinium, isoquinolinium, and N-acylpyridinium salts is also reported. [reaction: see text]
Subject(s)
Cyanides/chemistry , Nicotinic Acids/chemical synthesis , Nitriles/chemical synthesis , Pyridinium Compounds/chemical synthesis , Amides/chemistry , Niacinamide/chemistry , Quinolinium Compounds/chemical synthesis , StereoisomerismABSTRACT
Two novel tyrosinase mediated drug delivery pathways have been investigated for the selective delivery of cytotoxic units to melanocytes from urea and thiourea prodrugs. The synthesis of these prodrugs is reported, as well as oximetry data that illustrate that the targets are substrates for tyrosinase. The stability of each of the prodrugs in (i) phosphate buffer and (ii) bovine serum is discussed, and the urea prodrugs are identified as lead candidates for further studies. Finally, HPLC studies and preliminary cytotoxicity studies in a melanotic and an amelanotic cell line, that illustrate the feasibility of the approach, are presented.
Subject(s)
Drug Delivery Systems/methods , Melanocytes/drug effects , Melanoma/drug therapy , Prodrugs/chemical synthesis , Aminophenols , Cell Line, Tumor , Cell Survival/drug effects , Dopamine/analogs & derivatives , Drug Screening Assays, Antitumor , Humans , Monophenol Monooxygenase , UreaABSTRACT
[reaction: see text] The development of two novel protecting groups for amines is described. Thus, a range of amines have been converted to ureas, and the deprotection of these upon exposure to mushroom tyrosinase (E.C. 1.14.18.1) has been demonstrated.
