Coordination compounds in medicinal chemistry
Introduction
The essential role of transition metal ions in biological systems is well known [1], [2], [3], [4], [5], [6], [7]. In this paper we review issues that are important to development of transition metal complexes as pharmaceuticals. When designing metal complexes for therapeutic use the following events need to be considered: hydrolysis→protein binding→membrane transport→molecular target. Hydrolysis of metal complexes is important because of the aqueous milieu of biological systems, but the hydrophobic nature of cell membranes, vesicles and enzyme active sites requires consideration of lipophilic ligands in the design of complexes. Therefore, design of metallo-drugs requires bringing together organometallic chemistry with traditional aqueous coordination chemistry, a merger that is in its infancy [8], [9], [10]. Whether or not the ultimate target of a metallo-drug is a protein, protein binding is always a factor in the medicinal use of such compounds. For example. blood proteins such as albumin and transferrin have structural domains that strongly bind metal ions [11]. The greatest hurdle, however, is transport of metal complexes through cell membranes, which determines if metals enter cells with their ligands intact.
Development of metal complexes as pharmaceuticals has been slow in coming due to a prior belief that metal ions are not transported across cell membranes but are incorporated at the formation stage of cells [12]. Evidence for transport in mature cells first appeared in 1939 when K+ [13] and Na+ [14] were shown to move across red cell membranes in opposition to concentration gradients (i.e. active transport). It took twenty years longer before active transport of Ca+2 [15] was reported, while for Mn+2 the entry and exit remained a process of passive diffusion involving no carriers, transport, or metabolic linkage [16], [17]. In 1996 active transport of Mn+2 was reported [18], and in 1997 the trans-membrane protein DCT1 which transports Mn+2 and other transition metal ions was reported [19]. DCT1 is selective for divalent charge and is insensitive to electron configuration of the metal ions it transports. This suggests the protein provides a micro-environment where metal charge is balanced by charge on the protein positioned at or near optimum Debye lengths [20]. Movement of metal ions along the protein is coupled to H+ transport and the electrochemical potential across the cell membrane [19]. To what extent the protein allows transport of metal bound ligands is not known.
Section snippets
Iron
Iron complexes were the earliest metal compounds to be studied in medicinal chemistry. They were and are used to treat hypochromic anemia caused by iron deficiency. Clinical experience has revealed Fe(II) to be better absorbed than Fe(III) when given orally for this disease [21].
The first mechanism identified for transport of Fe(II) through cell membranes was endocytosis [22]. In this process transferrin, an Fe(II)-protein complex, is internalized by cell membranes as the protein binds to
Platinum
Acceptance of metal complexes as drugs was dramatically advanced by the use of Pt(II) complexes to treat testicular and ovarian cancers. This began in1965 with a report by Rosenberg, Van Camp and Krigas [45] that some Group VIIIb metal complexes inhibit cell division, and quickly lead to study of Pt(II) complexes as agents capable of stopping tumor growth [46]. The first Pt(II) complex to be licensed for this purpose was cisplatin, cis-[Pt(NH3)2Cl2]. For a history of cisplatin development see
Titanium
The earliest reference to medicinal chemistry of Ti(IV) is by the German physician Julius Pick [98]. He found Tiandisulfataufschwemmlosung (hydrolyzed Ti(SO4)2) and Ti(IV) mono- and di-salicylates were effective topical and oral treatments for Tuberkelbacillen infections. Pick studied a variety of Ti(IV) complexes with organic acids and other organic compounds such as Kresol, Thymol, α und β Naphtol, which were tested in animals before settling on titanium sulfate and salicylates as being
Conclusions
There is a large amount of data in the literature showing uptake of transition metal ions by mammalian cells, but little is known about the molecular mechanisms by which this happens [19]. Discovery of the trans-membrane protein DCT1 [19] is an important step toward unraveling these mechanisms; but what are the structural components of this protein that permit transport and what type of ligands are transported with the metal ion? As for uptake of metal ions by endocytosis; are metal ion
Acknowledgements
Our work with Ti(IV) was supported by the Francis and Russell Lucas Family Trust. We would like to thank the Reference Departments at Francis A. Countway Library of Medicine and the Cabot Science Library at Harvard University for their help.
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Present address: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.