Metallo‐Drugs and Their Action

Abstract

Introduction of metallo-drugs into the body exposes them to reaction with many substances in the biological system. While the main targets for these agents are proteins and DNA, passage through the blood and eventually into the cell allows the metal complex to come in contact which substances that can modify its composition. The main focus of this chapter is on giving a brief overview of the structures of proteins and DNA and summarizing the ways in which these important biomolecules react with metal ions. Since many metalcontaining agents used in medicine have easily-displaced ligands, the manner in which complexes react with simple ions found in the blood and cells will also be presented and discussed. In addition to highlighting the biological chemistry of metallo-drugs, it is also important to outline how their pharmacological effects are measured and, since there is increasing demand for more effective agents, how a discovery made in the laboratory makes its way through the approval process to become a drug. Proteins as targets for metallo-drugsThe human body has tens of thousands of different proteins, involved in a variety of different catalytic, transport and structural roles. If a metal ion introduced into the body in the form of a metallo-drug attaches itself to a part of the protein that is critical for function, the ability of the protein to perform its biological task could be impaired, which could be enough to kill the cell. For example, many catalytically-active proteins called metallo-enzymes have naturally-occurring metal ions such as Zn þ2 or Cu þ1/þ2 in their active sites. Since the same ligands on the protein that bind to the naturally-occurring metal ion could also serve as donor atoms to the metal ion in a metallo-drug, addition of the drug to the protein could result in displacement of the natural metal ion, causing the enzyme to be catalytically inactive. Many proteins in the body use metal ions as a means of organizing their structure. Since some of these metallo-proteins are involved in gene expression and interact directly with DNA, disruption of their structure by substituting the natural metal ion with one supplied by a metallo-drug could affect the specificity and affinity of the interaction, thus influencing the ability of the cell to make the proper proteins for survival. Metals in MedicineJames C. DabrowiakStructurally, proteins are long polyamide polymers that are made up of monomer units called amino acids, the structures of which, along with their three-and one-letter amino acid codes, are shown in Figure 2.1. As is evident in the figure, all of the amino acids have an amino, a carboxylic acid and a hydrogen atom attached to the a-carbon atom of the compound, but the forth group on the a-carbon, called the side chain, characterizes each amino acid. Except for glycine, all of the common amino acids have four different groups attached to the a-carbon atom, which makes the atom, and thus the amino acid, chiral. With the exception of cysteine, which has the R absolute configuration...