Targeting melanoma via metal based drugs: Dithiocarbamates, disulfiram copper specificity, and thiomaltol ligands.

摘要

Melanoma have an unusual susceptibility to certain lipophilic metal complexes, which is likely due to the pro-oxidant effect of metal ions on their indogenous catecholic pigment, melanin. Our hypothesis is the toxicity of metal ions to melanoma works via this pro-oxidant response of the pigment. An initial screening of cellular activity to identify new candidates for melanoma chemotherapy, indicated disulfiram (DSF) as apotential drug. DSF is commonly know as antabuse, the alcohol deterrent drug. Disulfiram, a dithiocarbamate (DTC) disulfide, has strong activity against melanoma cell lines which is Cu-dependent. Under almost all aqueous conditions the reaction of DSF and Cu2+ ions cannibalistically consume DSF molecules to produce the corresponding copper complex, Cu(deDTC)2 in high yield. The research focus subsequently turned toward the complexes themselves.; DTCs are strong bi-dentate metal chelators that have shown anti-melanoma activity, believed to be directly related to metal up-take and the oxidative processes within melanoma cells. Numerous DTCs were synthesized to probe the structure/activity relationship of DTCs. We propose that upon oxidation of the metal bound DTC ligand and sulfur extrusion, the metal is released within the cell inducing apoptosis. To probe the ROS nature associated with melanoma various oxygenated DTC zinc complexes were synthesized. Mono-oxygenated zinc complexes show increased activity, suggesting that S-oxygenation and sulfur extrusion are a pathway for metal-release within the cell. DTCs are widely used as pesticides and have inherent biological toxicity associated with them. Our research then shifted toward the synthesis of metal chelators with similar binding properties, which lack an inherent toxicity.; Maltol (Hma) is a nontoxic cyclic condensed sugar capable of chelating metals in a monanionic bidentate fashion. Thionation of maltol with sulfur delivery reagents like Lawesson's Reagent (LR) provided the previously known, but relatively obscure ligand thiomaltol (Htma) ligand. The use of LR led to the discovery of a new reaction, termed heterocyclic atom exchange reaction (HAER) yielding a previously unknown ligand, 3-hydroxy-2-methyl-4H-thiopyran-4-thione or dithiomaltol (Httma). The synthesis, structure, absorbance spectroscopy, ligand protonation constants, metal binding constants, and melanoma activity of several metals complexes of both the thio- and dithiomaltol complexes are discussed.