N-alkyl-N-dithiocarboxy-D-glucamine analogs as cadmium antagonists: synthesis and evaluation of the n-propyl, n-butyl, and n-amyl derivatives.
N-(n-Propyl)-, N-(n-butyl)-, and N-(n-amyl)-N-dithiocarboxy-D-glucamine were newly synthesized by (a) addition of each n-alkylamine to glucose, (b) high-pressure catalytic reduction of each glucosamine thus formed to the corresponding glucamine, and (c) reaction of the resultant secondary amines with CS2 to form the dithiocarboxy derivatives. Each compound was evaluated as an antagonist of acute cadmium (Cd) toxicity and as a complexing agent for intracellular metallothionein-bound Cd (Cd-MT) in mice. N-Benzyl-N-dithiocarboxy-D-glucamine (BDCG) was used as a positive control compound. Each congener afforded partial or complete protection against the lethal effects of 10.0 mg/kg CdCl2.2.5 H2O, and retarded accumulation of Cd in livers and kidneys when given 2 h after the acutely toxic dose of Cd. Each derivative was also effective in mobilizing Cd from MT-bound sites in livers and kidneys of mice which had received a sub-lethal dose of CdCl2 along with 109CdCl2 2 weeks earlier. Excretion of mobilized Cd was almost exclusively by the fecal route. Potency of the analogs, as well as the octanol/aqueous partition coefficients, increased with the overall length of the N-(n-alkyl) carbon chain. Each compound readily complexed Cd from partially purified Cd-MT in vitro. Serum Cd from mice treated with BDCG was associated principally with proteins of high molecular weight.
Gale
G R
GR
Veterans Administration Medical Center, Charleston, South Carolina 29403.
Atkins
L M
LM
Smith
A B
AB
Jones
S G
SG
Basinger
M A
MA
Jones
M M
MM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008668:Metallothionein / Q000097:blood / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D012995:Solubility; D013012:Sorbitol / Q000031:analogs & derivatives*; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D014018:Tissue Distribution
D013859:Thiocarbamates; D002104:Cadmium; D013012:Sorbitol; D008536:Meglumine; D008668:Metallothionein