valence electrons very strongly; hard cations are not readily polarized and are of small
size and high charge. Conversely, a soft cation is relatively large, does not retain its
valence electrons firmly, and is easily polarized. Examples of hard cations include Li+,
Na+,K+,Ca^2 +,Fe^3 +,and Mn^2 +; examples of soft cations include Cu+,Ag+,Au+,Pd^2 +,and
Cd^2 +. Chelating ligands containing highly electronegative donor atoms (O, N, F) are dif-
ficult to polarize and can be classified as hard bases. Easily polarized ligands, contain-
ing phosphorus or sulphur, act as soft bases. Examples of hard ligands include OH-,
OR-, ROH, NH 3 , Cl-, F- and NO 3 -; examples of soft ligands include RSH, RS-, R 2 S,
R 3 P, SCN- and I-. As a general rule, the formation of stable chelates, or complexes,
results from interactions between hard acids and hard bases, or between soft acids and
soft bases. Hard–soft interactions are weak and less desirable.
A number of chelating agents are in clinical use. The chelates formed between the
chelating agent and the toxic metal are nontoxic and are excreted via the kidney. The
organometallic bond tends to be stable within the concentrated, acidic milieu of the renal
tubular urine, thus facilitating the urinary excretion of the metal ion. Ethylenediaminetetra-
acetate (EDTA) is the prototypic chelating agent. EDTA possesses four carboxylate
groups whose geometry enables the chelation of lead. Dimercaprol (9.127) (British Anti-
Lewisite, BAL) was developed during World War II as an antidote against arsenical
chemical warfare agents. Although it chelates a variety of metal ions, dimercaprol tends
to be chemically unstable and is administered intramuscularly in an oily vehicle.
Dimercaptopropane sulfonate (9.128) is a chemically stable analog of dimercaprol that
may be given orally. D-penicillamine (9.129) is a chelating agent that promotes the
removal of copper from the body.
Drug design for the treatment of toxins is a discipline that is probably still in its
infancy. We continue to introduce new chemicals into our environment; someday we
will be confronted with the health issues that will arise. Currently, antidotes are essentially
EXOGENOUS PATHOGENS AND TOXINS 595