Endothall thioanhydride: structural aspects of unusually high mouse toxicity and specific binding site in liver.
The thioanhydride of the herbicide endothall is highly toxic to mice on intraperitoneal (ip) administration, with an LD50 of 0.31 mg/kg compared to 4.0 and 14 mg/kg for the corresponding anhydride and dicarboxylic acid, respectively. This unusually high toxicity of the thioanhydride relative to the anhydride and dicarboxylic acid is observed also for the 5,6-dehydro analogue and less so for the 2-methyl and 5-endo-(cyanomethyl) analogues but not for five related series of 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acids, anhydrides, and thioanhydrides with various 2-, 3-, 5- and 6-substituents. Synthesis of [exo,exo-5,6-3H]endothall thioanhydride ([3H]ETA) allowed radioligand binding studies with mouse liver cytosol, which was found to have a high-affinity binding site (apparent dissociation constant 32 nM, maximum number of binding sites 2.8 pmol/mg of protein, greater than 95% specific binding). The potency of 18 endothall analogues as dicarboxylic acids and anhydrides for inhibiting [3H]ETA binding in vitro is a very good predictor of their mouse toxicity (r = 0.95, n = 16; two related compounds are of low activity in both assays) in a similar manner to earlier studies with [3H]-2,3-dimethylendothall anhydride (cantharidin) (r = 0.83, n = 15). This correlation does not extend to most of the thioanhydrides, particularly the 2,3-dimethyl and 2,3-trimethylene compounds, which are the most stable to hydrolytic cleavage. The [3H]ETA binding site of liver cytosol is inhibited 75-80% by LD50 doses of 2,3-dimethylendothall anhydride and thioanhydride but only 24% by an LD50 dose of endothall thioanhydride, with assays 30 min after ip treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Kawamura
N
N
Department of Entomological Sciences, University of California, Berkeley 94720.
Li
Y M
YM
Engel
J L
JL
Dauben
W G
WG
Casida
J E
JE
D000812:Anhydrides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D002193:Cantharidin / Q000633:toxicity; D003998:Dicarboxylic Acids / Q000378:metabolism / Q000633:toxicity*; D006868:Hydrolysis; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
D000812:Anhydrides; D003998:Dicarboxylic Acids; C100030:endothall; D002193:Cantharidin