Use of the Topliss scheme for the design of more effective chelating agents for cadmium decorporation.
The Topliss scheme, which designates a special series of substituents for use in sequence in the search for suitably substituted aromatic compounds with biological properties superior to the parent unsubstituted aromatic compound, has been applied to the design of new chelating agents for the decorporation of cadmium from its deposits in vivo. Substituted benzylamines have been used in the syntheses of the corresponding substituted sodium N-benzyl-D-glucamine-N-carbodithioates, i.e., RC6H4CH2N(CS2Na)CH2(CHOH)4CH2OH (or RBGDTC): CF3BGDTC, R = 3-CF3; MeBGDTC, R = 4-CH3; MeOBGDTC, R = 4-OCH3; ClBGDTC, R = 4-Cl. Examination of the behavior of these compounds as agents for the mobilization of cadmium from its deposits in vivo shows that such substitution can have an appreciable effect on the organ selectivity for cadmium removal, as well as the efficacy. Of the four compounds suggested by the Topliss scheme for pilot studies, two were much more effective than the parent compound (BGDTC), and of these the best one, sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate (MeOBGDTC) reduced kidney cadmium levels to 30% and liver cadmium levels to 50% of those obtained with the parent compound. Sodium N-[3-(trifluoromethyl)benzyl]-D-glucamine-N-carbodithioate (CF3BGDTC) was also found to be superior to the parent compound in reducing the liver cadmium levels, though it was equivalent in reducing renal cadmium levels.
Jones
S G
SG
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Singh
P K
PK
Jones
M M
MM
D000818:Animals; D002104:Cadmium / Q000378:metabolism*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
D002614:Chelating Agents; D013859:Thiocarbamates; D002104:Cadmium; D013012:Sorbitol; C048763:N-benzylglucamine dithiocarbamate