title: Chirality, charge, and chain branching effects on dithiocarbamate-induced mobilization of cadmium from intracellular deposits in mice.
abstract: The effects of three major structural features on the intracellular cadmium mobilizing potency of dithiocarbamates have been examined. These features, the chirality of the groups, the total ionic charge of the chelating agent, and the extent of chain branching, would be expected to affect the pharmacological properties of these chelating agents but to have little effect on the stability constants of the cadmium complexes involved. A total of 25 compounds (including 21 new ones) was prepared and used in animal studies designed to evaluate these effects. These included a series of amphipathic dithiocarbamates of the general type R1N(R2)CS2-Na+, where R1 is a relatively nonpolar organic group and R2 is derived from a reducing hexose. All of the factors examined influenced the potency of dithiocarbamates in the mobilization of cadmium from intracellular deposits. The compounds with R2 = galactose or mannose and R1 = benzyl were both more effective than the corresponding glucose derivatives in inducing the removal of cadmium from the liver and the whole body. Increases in the net negative charge of the chelating agent uniformly decreased the observed potency in the mobilization of hepatic and renal cadmium deposits. The replacement of a normal alkyl group by a branched-chain group of the same molecular weight also led to an increase in potency for the two pairs of compounds examined. Dithiocarbamates which are not amphipathic because of the presence of similar polar substituents for both R1 and R2, such as sodium diarabitylamine carbodithioate, were relatively ineffective as agents for the mobilization of intracellular cadmium.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: M M
authors.initials: MM
authors.lastname: Jones
authors.forename: P K
authors.initials: PK
authors.lastname: Singh
authors.forename: S G
authors.initials: SG
authors.lastname: Jones
authors.forename: C R
authors.initials: CR
authors.lastname: Mukundan
authors.forename: J A
authors.initials: JA
authors.lastname: Banton
authors.forename: G R
authors.initials: GR
authors.lastname: Gale
authors.forename: L M
authors.initials: LM
authors.lastname: Atkins
authors.forename: A B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013012:Sorbitol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D013859:Thiocarbamates; D002104:Cadmium; C060427:N-(4-methoxybenzyl)glucamine dithiocarbamate; D013012:Sorbitol; C048763:N-benzylglucamine dithiocarbamate