A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascid...
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A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50 = 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents, Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials, The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.
The three fungicides, captan, captofol and folpet and a structurally related compound, thalidomide, were investigated for possible mutagenic activity by the dominant lethal mutagenicity study in mice and by the host-m...
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The three fungicides, captan, captofol and folpet and a structurally related compound, thalidomide, were investigated for possible mutagenic activity by the dominant lethal mutagenicity study in mice and by the host-mediated assay in rats using a histidine auxotroph of Salmonella typhimurium . Male mice were treated with a single ip injection of captan (3 or 6 mg/kg), captofol (1·5 or 3·0 mg/kg), folpet (5 or 10 mg/kg) or thalidomide (50 or 1000 mg/kg). The results of weekly matings with untreated virgin females disclosed no increase in early embryonic death among conceptuses obtained from females mated with the treated males. Groups of male rats were treated by oral intubation for 14 days with one of the three fungicides at levels of 125 or 250 mg/kg/day or with thalidomide at 500 or 1000 mg/kg/day. Indicator micro-organisms recovered from the peritoneal cavity of the treated male rats after a 3-hy residence showed no increase in numbers of revertants. Thus captan, captofol, folpet and thalidomide were not mutagenic in either of these test systems.
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