STUDIES ON SUBSTITUTED DITHIOOXAMIDES, DIPHOSPHOPYRI DINE NUCLEOTIDE-LINKED DEHYDROGENASE INHIBITORS I. GENERAL TOXICITY AND SITE OF ACTION

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, and Biochemical Research Department, Dow Chemical Company, Midland, Michigan

The toxicities of dithiooxamide, N , N'-bis (2-hydroxyethyl) dithiooxamide, N , N'-diallyldithiooxamide, and N , N'-di-secondary butyl dithiooxamide were studied. The diallyl and secondary butyl derivatives proved to be toxic whereas dithiooxamide and the 2-hydroxyethyl derivative failed to show any toxicity at doses of 50 mgm./kgm. The toxicity of the potent compounds is characterized by cardiac arrhythmias and central nervous system disturbances. Death is more often the result of ventricular fibrillation. Other characteristics of the potent derivatives are a latent period, extreme cumulative toxicity and the lack of significant species variation among mammals.

The in vitro biochemical effects of these compounds were examined. Only the toxic compounds proved to be active in vitro. The in vitro activity was limited to the inhibition of coenzyrne I-linked enzymes in mitochondrial and purified enzyme systems. These enzymes are suggested as the site of action of the potent dithiooxamides.