N-Alkyl-N-dithiocarboxy-d-glucamine analogs as cadmium antagonists: synthesis and evaluation of the n-propyl, n-butyl, and n-amyl derivatives

Abstract

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.