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Metallodrugs in Medicine: Present, Past, and Future Prospects

Imtiyaz Yousuf* and Masrat Bashir

Department of Chemistry, Aligarh Muslim University, Aligarh, India

Abstract

Metal coordination complexes on account of their unique properties of metals which includes variable oxidation states, geometry, coordination numbers, redox behavior, and ability to bind to a wide variety of types of ligands offer a versatile platform for the design of novel therapeutic and diagnostic agents. The therapeutic potential of metal ions can be optimized by tethering it to a suitable frame work that not only tune but synchronize the organic ligand scaffold to act in concord at the target site. Medicinal inorganic chemistry is a growing interdisciplinary field of pharmaceutical research which involves design of therapeutic and diagnostic agents with emphasis on medicinal use for the treatment of various chronic diseases. The serendipitous discovery of cisplatin, inorganic anticancer drug opened up new prospects in the area of medicinal inorganic chemistry that not only cured cancer but provided a continuous spur towards the development of new metallodrugs that can address the serious challenges in the drug regime. Thus, many metal-based therapeutics and diagnostic agents have been explored extensively for their diverse applications as artificial metalloenzymes, DNA foot-printing agents, and nucleic acid structural probes, etc. Given the premises of metallodrugs in the medicinal field, this chapter focuses on the progress made by metal-based drugs as anticancer, anti-bacterial, anti-viral, anti-inflammatory, and anti-neurodegenerative agents, as well as emphasis on the new strategies to be used in the development of new potential metallodrugs.

Keywords: Medicinal inorganic chemistry, metallodrugs, metal-coordination complexes, therapeutic and diagnostic agents, chronic diseases, drug delivery, prodrugs

1.1 Introduction

Medicinal inorganic chemistry is an interdisciplinary sub-area of bioinorganic chemistry field which tethers the applications of inorganic chemistry and biological disciplines, thereby investigate the intriguing properties of metal ions, their complexes, and other metal binding compounds for the therapeutic and diagnostic purposes [1-6]. Conceptually, the field of medicinal inorganic chemistry includes the biomimetic chemistry of metal ions in metalloproteins [7, 8], identification of metal ions in pathogenic protein misfolding [9, 10], functions of endogenous and exogenous metal ions at the molecular level [11, 12], and the homeostasis of metal ions in living systems [13]. The use of several metals (Cu, Au, Ag, Hg, and As) can be traced back to ancient civilizations (Mesopotamia, Egypt, India, and China) [14] with the recognition by the Egyptians who used copper to sterilize water with an understanding of disinfection and the Chinese and Arabs utilized gold in the treatment of many chronic diseases [15]. Zinc was found to promote healing of wounds while mercurous chloride was used as a diuretic. Paul Ehrlich the "founder of chemotherapy" developed arsenical, Salvarsan, as a drug for the treatment of Syphilis in early twentieth century (Figure 1.1) [16]. Thus, a link between the discovery of a new elements and their application into the medicinal armamentarium (therapeutic and diagnostic) has been exploited since antiquity (Table 1.1).

Numerous metal ions and their complexes have been routinely administered to patients for therapeutic and diagnostic benefit such as platinum and ruthenium complexes in cancer therapy [17-20], gold complexes as anti-arthritis agents [21, 22], cobalt complexes as antiviral [23], and gadolinium and technetium as magnetic resonance imaging (MRI) contrasting agents [24-26] (Figure 1.2).

Metal ions can serve many important functions in the biological systems; (i) functional role, i.e., the biological activity is due to direct binding of the metal fragment to the target site [27], (ii) structural role, i.e., the shape of the complex is determined and binding to the biological target occurs through non-covalent interactions [28-30], (iii) act as a carrier for active ligands that are delivered in vivo [31, 32] and protect the ligand before its delivery at the target site, (iv) metal complexes behave as a catalyst in vivo by the production of reactive oxygen species (ROS) that cause cell damage [33, 34], and (v) metal complexes which are photoactive can act as photosensitizers [35, 36]. Metal ions once introduced into a bio system for therapeutic or diagnostic effect can also be removed from back by the judicious use of the chelating ligands (chelation therapy). Many proteins and enzymes bind one or more metal ions to perform their functions where the metal ion is involved in the catalytic mechanism or stabilizes the tertiary and quaternary structure of proteins.

Figure 1.1 Structures of arsenic-based therapeutic drug, salvarsan (3?amino?4? hydroxyphenyl?arsenic(III) compounds).

Table 1.1 The use of metal salts and their compounds as therapeutic and diagnostic agents.

Figure 1.2 Prominent examples of metal-based drug in medicinal inorganic chemistry: (a) Cisplatin, (b) MS-325, (c) Darinaparsin, and (d) Auranofin.

Whereas the small organic drug molecules rely purely on carbon, their binding geometry in space is dictated by the hybridization, viz., sp (linear), sp2 (trigonal-planar), and sp3 (tetrahedral) as compared to the diverse geometry in 3D space open to metal-based drugs [37]. Besides linear, square planar, and tetrahedral geometries, pyramidal, trigonal bipyramidal, and octahedral shapes can be created and even higher coordination numbers and geometries with larger metal ions are possible, all of these geometries exhibit a tremendous importance for biological phenomena that allow the fine-tuning of their chemical reactivity in terms of both kinetics (rates of ligand exchange) and thermodynamics (strengths of metal-ligand bonds, redox potentials, etc). Not only the metal but also the ligands can play important roles in biological activity, ranging from outer-sphere recognition of the target site to the activity of any released ligands and ligand centered redox processes. Modification of substituents or ligands around the metal center, thus modulates drug entities to perform...