Med

Med. of known profile in human body, low-cost, little side effects and high selectivity against different cancers and synergistic activity with other drugs. Many of the biological properties of DSF seem to require its complexation with metals. About 50 years of use is reported of DSF as an antialcoholism drug and now is being used in the treatment of cancer [3C10]. NS-018 The pharmacology of DSF in patients and cell lines is well-known [11]. DSF is a promissory drug against cancer because of easy availability, cost effectiveness and less adverse effects than classical drugs cancerostatics. Another important characteristic is the ability of DSF to show tumor proteasome activities thud representing a new, promising approach to proteasome inhibition. In addition, DSF is also able to suppress different cancer-associated pathways including ROS, PIK, MAPK, NF-B, IFNA ALDH, EGFR/Src/VEGF and others [12, 13]. 2.?CHEMICAL ASPECTS 2.1. General Structures of Dithiocarbamates and Disulfiram 2.1.1. Dithiocarbamates (DTC) Dithiocarbamates (DTC) belong to a class of compounds known as 1,1-dithiolates, that include dithiophosphates, dithiopohosphinates, dithiocarbimates and other related compounds. DTC compounds comprise a large group of molecules having condensed structure R1-R2-NCSS-R3, which are chemically the semiamides of dithiocarbonic acid or dithioacids of low molecular weight [14]. The structures in Fig. (1) shows a distribution of four canonical forms of the dithiocarbamate ligands, all having an IR band in the regions 1480C1550 cm?1 corresponding to C-N bond and UV-Vis band in the regions 450 nm assignating to C-S2? bond, which appear and can be changed when they form a metal-containing complex [15]. These compounds can be easily synthetized from primary or secondary amines, and should have good solubility in water or organic solvents depending upon the nature of the cation [16]. Open in a separate window Fig. (1). Structures of resonance of dithiocarbamates. One important characteristic of these compounds is their ability to be amphiphilic, lipophilic or hydrophilic depending to the R-substitutions. Normally, bifunctional or unifunctional compounds are present in these groups, which means that two different or equal chemical entities can be found in the same molecule resulting in different chemical and physical properties. For example, solubility of such a compound in both water and octanol/water mixture can be used to predict whether and how it could cross cellular membrane [17]. DTC salts are soluble in water and relatively insoluble in common organic compounds and are stable under basic and neutral conditions. However, in some cases, they can be decomposed to form isothiocyanate (basic conditions), amines, and CS2 (acid conditions). DTC can also undergo oxidation to form thiuram disulfide, through a pathway a single electron detachment [18]. 2.1.2. Disulfiram (DSF) Disulfiram (DSF, Fig. 2) or tetraethylthiuram disulphide is a disulfide derivative of DEDTC. The chemical formula of DSF is C10H20N2S4 or ((C2H5)2NCS)2S2. DSF is more lipophilic than DEDTC, an important feature of DSF is that it can cross cellular membrane more easily than DEDTC. Therefore, DSF is a better drug than DEDTC for the potential treatment of human diseases. NS-018 Open in a NS-018 separate window Fig. (2). Structure of Disulfiram. DSF can be decomposed under acidic conditions or upon reduction of its disulphide bridge to yield two diethyldithiocarbamate molecules which can then chelate copper and induce stimulation of Reactive Oxygen Species (ROS) by copper. Additionally, DSF could produce Reactive Nitrogen Species (RNS) NS-018 (Fig. 3) [19]. Open in a separate window Fig. (3). Products of decomposition of Disulfiram. The super reactivity of dithiocarbamates and disulfiram, is mainly related with two aspects. One aspect is their ability to chelate metals generally forming stable complex (do not inhibit proliferation in cancer cell lines which could be explained when UV-Vis spectra is studied. These compounds did not show a characteristic band at wavelenght 450 nm specific to S-Metal.