Structureactivity relationship with therapeutic chelating agents

Abstract

Although the vast majority of therapeutic chelating agents are water soluble rather than lipid soluble (e.g. EDTA, D-penicillamine, DTPA, desferrioxamine and unithiol, among others,) recent studies [1, 2] have shown that lipid soluble chelating agents and those that give soluble metal chelates, may be the only effective means of mobilizing intracellular deposits of certain metals. This has been shown most strikingly in the case of cadmium present in the kidney (as metallothionein). Such deposits can be mobilized by both BAL and sodium diethyldithiocarbamate. Because it is possible to synthesize derivatives of sodium diethyldithiocarbamate with varying lipophilicity, we have undertaken to prepare some of these compounds and examine their behavior as antidotes for acute cadmium intoxication. The animal experiments have been carried out using procedure of Gale et al. [2, 3], while syntheses have been done using published procedures [4]. The dithiocarbamates prepared and examined are shown in Table I, together with information on their efficacy as antidotes. The behavior of these compounds as antidotes can be correlated using the pi substituent constants of Hansch, as tabulated by Chu [5]. For each compound the relative hydrophobic nature can be estimated as the sum of the pi substituent constants of R 1 and R 2. These sums are shon in the last column of Table I. Figure 1 below shows the survival ratio variation with Σπ. One of the adverse effects of such dithiocarbamates is their ability to transport cadmium to the brain, an effect which is also related to the lipophilicity of the chelating agent. If the Net Efficacy of the chelating agent is defined as ▪ t001 Antidotal Behavior of Dithiocarbamates ( −S 2CNR 1R 2) Compd. R 1 R 2 Relative Survival Ratio a Relative Brain Cd b Σπ A C 2H 5 C 2H 5 1.00 1.00 2.04 B CH 3 CH 3 1.00 0.88 1.12 C C 2H 4OH C 2H 4OH 0.88 0.30 −1.54 D CH 3 CH 2COO − 0.63 0.14 −4.16 E CH 3 C 2H 4OH 1.00 0.00 −0.21 F CH 2COO − 0.38 0.02 −5.44 a Relative Survival Ratio = Survival Rate/Survival Rate for A. b Relative Brain Cd = Brain Cd/Brain Cd for A. ▪ then such a net efficacy (with n = 2), as plotted in Fig. 2, can be seen to reach a maximum in the region Σπ≈0. It is possible that such correlations will prove useful in the development of optimal chelating agents for the removal of intracellularly deposited metal ions.