Meso-2,3-dimercaptosuccinic acid mono-N-alkylamides: syntheses and biological activity as novel in vivo cadmium mobilizing agents.
Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.
Singh
P K
PK
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA.
Jones
M M
MM
Rostial
K
K
Blanusa
M
M
Piasek
M
M
Restek-Samarzija
N
N
D000577:Amides / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002104:Cadmium / Q000008:administration & dosage / Q000032:analysis* / Q000633:toxicity; D002614:Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000633:toxicity*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013012:Sorbitol / Q000008:administration & dosage / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D004113:Succimer / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000633:toxicity; D013859:Thiocarbamates / Q000008:administration & dosage
D000577:Amides; D002614:Chelating Agents; D013859:Thiocarbamates; D002104:Cadmium; D013012:Sorbitol; D004113:Succimer; C048763:N-benzylglucamine dithiocarbamate