In vivo cadmium mobilization by three novel bis(carbodithioates).
Four novel cadmium-chelating agents N,N'di(D-glucosyl)alkanediamine-N,N'-bis(carbodithioates) 4a-e were prepared as disodium salts of the general formula (CH2)n[N(CS2Na)CH2(CHOH)4CH2OH]2, where n = 7, 8, 10, and 12. They were synthesized by the reductive coupling of 2 mol of alpha-D-(+)-glucose (1) with 1 mol of the corresponding alkanediamines 2a-e followed by reaction with CS2 in a basic medium. The elemental analyses of the Cd complexes 5a, b, d, and e prepared revealed that these bis(carbodithioates) form 1:1 complexes with Cd2+. The in vivo cadmium-mobilizing efficacy of three of the new chelators (4a, b, and d) was determined in rats pretreated ip with CdCl2.H2O containing 2 microCi of 109Cd (74 kBq), and comparable data were obtained on a previously reported member of this series (4c, n = 9), and with BGDTC (sodium N-benzyl-D-glucamine-N-carbodithioate, 6), all given once at 1.0 mmol/kg ip. The compound with n = 12 (4e, C12G2DTC) proved to be too toxic in the preliminary study and was not evaluated further. A single injection of the 4a, b, and d caused a reduction in Cd levels of the whole body to ca. 50% and liver to ca. 12% of control levels. Comparable experimental data on BGDTC resulted in a reduction of whole-body cadmium to only 78% of the control levels and a reduction in liver cadmium to only 56% of control. After one and six injections at the same dosage, the new chelators (4a, b, and d) and C9G2DTC (4c, n = 9) significantly surpassed BGDTC for whole-body and liver Cd depletion but caused only a very modest depletion of renal Cd. While these compounds were designed to allow the two dithiocarbamate groups to coordinate to the same Cd2+ in vivo, the data do not prove that the two > NCS2Na groups bind to the same cadmium ion in vivo. The very rapid reduction in liver cadmium levels following only a single injection indicates that these -2 anions rapidly gain access to intracellular hepatic sites by some transport system.
Singh
P K
PK
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA.
Jones
M M
MM
Kostial
K
K
Blanusa
M
M
Piasek
M
M
D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics* / Q000633:toxicity; D002106:Cadmium Radioisotopes / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000493:pharmacokinetics*; D005260:Female; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000493:pharmacokinetics*
D002106:Cadmium Radioisotopes; D002614:Chelating Agents; D013859:Thiocarbamates; D002104:Cadmium; D013012:Sorbitol; C048763:N-benzylglucamine dithiocarbamate