1,2-DITHIOL-3-THIONE AND DITHIOESTER ANALOGS - POTENTIAL RADIOPROTECTORS

Several l, 2-dithiol-3-thione and dithioester compounds were assayed for radioprotective capabilities in EMT6 cells in vitro. The l, 2-dithiol-3-thiones were generally more cytotoxic than the dithioesters and in some instances were more cytotoxic toward hypoxic cells than toward normally oxygenated cells. When the drugs were present at a concentration of 500 μM for 1 h prior to and during radiation delivery, the 5-(2-thienyl)-l, 2-dithiol-3-thione produced a radiation protection factor (RPF) of 2. 7 at 1 log of cell kill. The 4-methyl analogue of this same compound was, however, much less effective, producing a RPF of only 1. 2. The 4-ethoxycarbonyl analogue was moderately active, producing a RPF of 1. 7. The 4-methyl-5-(2-pyrazinyl)-dithiol-3-thione (Oltipraz) was least effective, yielding a RPF of only 1. 1. Of the dithioesters tested, methyl 3-pyrrolidino-2-phenylpropene dithiocarboxylate produced a RPF of 2. 6, methyl 3-piperidino-2- phenylpropenedithiocarboxylate a RPF of 2. 7, and the corresponding 3-morpholino and 3-thiomorpholino derivatives RPF values of 2. 7 and 2. 9, respectively. The iodide salt of 4-ethoxycarbonyl-5-(2-thienyl)-l, 2- dithiol-3-thione produced a RPF of 2. 6 Methyl 3-cyclohexylamino-2-phenylpropenedithiocarboxylate was equally effective (RPF = 2. 6). Finally, methyl 3-morpholino-3-thienyl-2-methylpropenedithiocarboxylate and methyl 3-morpholino-3-(2-pyrazinyl)-2-methylpropenedithiocarboxylate were less effective, producing RPF values of 2. 0 and 1. 6, respectively. These results demonstrate that several of these compounds are highly effective radioprotectors. In vitro and in vivo studies testing their efficacy are underway. © The MacMillan Press Ltd., 1990.