Design of in vivo cadmium-mobilizing agents: synthesis and properties of monobenzyl meso-2,3-dimercaptosuccinate.
A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.
Jones
M M
MM
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Singh
P K
PK
Basinger
M A
MA
Gale
G R
GR
Smith
A B
AB
Harris
W R
WR
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D002104:Cadmium / Q000378:metabolism* / Q000652:urine; D002614:Chelating Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D051381:Rats; D017207:Rats, Sprague-Dawley; D004113:Succimer / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013386:Succinates / Q000378:metabolism / Q000652:urine; D013431:Sulfates / Q000378:metabolism / Q000652:urine; D010130:p-Aminohippuric Acid / Q000378:metabolism / Q000652:urine
D002614:Chelating Agents; D013386:Succinates; D013431:Sulfates; C089228:monobenzyl 2,3-dimercaptosuccinate; D002104:Cadmium; D004113:Succimer; D010130:p-Aminohippuric Acid