**1. Introduction**

Organometallic chemistry deals with three basic aspects as environmental concern, biological aspect, and medicinal chemistry. Medicinal organometallic chemistry continues to be a major application for these compounds in biology. Medicinal organic chemistry has therapeutics, diagnostics, and theranostics effects. Medicinal organometallic complexes consist of platinum, ruthenium, iron, titanium, and gold among other metals. Fundamental studies have been carried

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out on the organometallic complexes in which the mechanism of action exert their medicinal effect (e.g., induce cell death in cancer cells), the synthesis of new organometallic compounds and the development of combination therapies containing organometallic components. Research has shown significant progress in utilization of transition metal complexes as

#### **1.1. Anticancer agents**

The development of metal complexes with platinum as a central atom such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. Cisplatin has become one of the most widely used drugs and is highly effective in treating several cancers such as ovarian and testicular cancers. The limitations of cisplatin have stimulated research in the field of platinum antitumor chemistry by including the reduction in toxicity of cisplatin (nausea, ear damage, vomiting, loss of sensation in hands, and kidney toxicity), acquired drug resistance observed in certain tumors and inefficiency of the drug against some of the commonest tumors (e.g., colon and breast). Due to its particular chemical structure, cisplatin offers little possibility for improvement in tumor specificity and thereby reducing side effects. The other alternative complexes have at least one direct, covalent metal-carbon bond, having structural variety, diverse stereochemistry, provide control over major kinetic properties, kinetically stable, usually uncharged, and having low oxidation state of metal atom, so they can be used as ideal candidates for anticancer candidates [1–4]. Some examples are: metallocenes [5–9], organometallic ruthenium half-sandwich complexes [10–14], organometallic osmium half-sandwich complexes [15–17], organometallic iridium and rhodium complexes [18–21], rhenium organometallics [22–24], ruthenium, osmium, iridium, and platinum organometallics as scaffolds for protein kinase inhibitors, metal NHC complexes [25, 26], and metal carbonyl complexes [27, 28].

#### **1.2. Antibacterial agents**

The biggest challenge in the antibacterial market is the issues related to the drug-resistant pathogens. The remedy is now to search for new compounds with new mode of action to overcome the resistant strains. This can be done by either the organic derivatization of old drugs or completely new organometallic drugs, for example, new tamoxifen [19–21, 29], platensimycin [22–24], etc.

#### **1.3. Anti-infectant agents**

Transition metal as silver is being used as the antimicrobial agent due to its low toxicity as compared to the other metals. For example: silver (1) sulfazine, which is used to treat burns to prevent the bacterial infections. Silver nitrate is given to the infants to prevent the development of ophthalmia neonatorum. Chlorhexidine-silver sulfadiazine is an anti-infective metal complex against catheter infections. Organometallic complexes of Pt [30–32], Rh, Ir, Pd, and Os metal with active organic molecules have been reported to exhibit trypanocidal activity. Metal complexes of Pt (II) and Ru (II) with o-vanillin-(4-methyl thiosemicarbazone), and o-vinillin-(4-phenyl thiosemicarbazone), metal complexes of Ga (III), Al (III), and Fe are among the various other drugs [33–36].

#### **1.4. Anti-inflammatory agents**

out on the organometallic complexes in which the mechanism of action exert their medicinal effect (e.g., induce cell death in cancer cells), the synthesis of new organometallic compounds and the development of combination therapies containing organometallic components. Research

The development of metal complexes with platinum as a central atom such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. Cisplatin has become one of the most widely used drugs and is highly effective in treating several cancers such as ovarian and testicular cancers. The limitations of cisplatin have stimulated research in the field of platinum antitumor chemistry by including the reduction in toxicity of cisplatin (nausea, ear damage, vomiting, loss of sensation in hands, and kidney toxicity), acquired drug resistance observed in certain tumors and inefficiency of the drug against some of the commonest tumors (e.g., colon and breast). Due to its particular chemical structure, cisplatin offers little possibility for improvement in tumor specificity and thereby reducing side effects. The other alternative complexes have at least one direct, covalent metal-carbon bond, having structural variety, diverse stereochemistry, provide control over major kinetic properties, kinetically stable, usually uncharged, and having low oxidation state of metal atom, so they can be used as ideal candidates for anticancer candidates [1–4]. Some examples are: metallocenes [5–9], organometallic ruthenium half-sandwich complexes [10–14], organometallic osmium half-sandwich complexes [15–17], organometallic iridium and rhodium complexes [18–21], rhenium organometallics [22–24], ruthenium, osmium, iridium, and platinum organometallics as scaffolds for protein kinase inhibitors, metal NHC

The biggest challenge in the antibacterial market is the issues related to the drug-resistant pathogens. The remedy is now to search for new compounds with new mode of action to overcome the resistant strains. This can be done by either the organic derivatization of old drugs or completely new organometallic drugs, for example, new tamoxifen [19–21, 29], pla-

Transition metal as silver is being used as the antimicrobial agent due to its low toxicity as compared to the other metals. For example: silver (1) sulfazine, which is used to treat burns to prevent the bacterial infections. Silver nitrate is given to the infants to prevent the development of ophthalmia neonatorum. Chlorhexidine-silver sulfadiazine is an anti-infective metal complex against catheter infections. Organometallic complexes of Pt [30–32], Rh, Ir, Pd, and Os metal with active organic molecules have been reported to exhibit trypanocidal activity. Metal complexes of Pt (II) and Ru (II) with o-vanillin-(4-methyl thiosemicarbazone), and o-vinillin-(4-phenyl thiosemicarbazone), metal complexes of Ga (III), Al (III), and Fe are

has shown significant progress in utilization of transition metal complexes as

complexes [25, 26], and metal carbonyl complexes [27, 28].

**1.1. Anticancer agents**

4 Recent Progress in Organometallic Chemistry

**1.2. Antibacterial agents**

tensimycin [22–24], etc.

**1.3. Anti-infectant agents**

among the various other drugs [33–36].

These complexes are also used as anti-inflammatory and antiarthritic agents. Several injectable transition metal complexes as sodium aurothiomalate, aurothioglucose, sodium aurothiopropanol and gold and silver nanoparticles conjugated with heparin derivative possess antiangiogenesis properties [37–39]. Gold has been used for the treatment of peripheral psoriatic arthropathy. As a product of oxygen metabolism, superoxide anion can trigger oxidative injury to tissues. This activity is associated with riper fusion and inflammatory diseases as well as neurological disorders such as Parkinson's disease and Alzheimer's disease. However, excess use of these complexes in arthritis causes pain and fever. NO is excellent ligand for transition metal ions and these metal nitrosyls having therapeutic values. Sodium nitroprusside is used to treat cardiovascular diseases by releasing NO with limited usage due to the toxicity of CN− . Ruthenium poly aminocarboxylate complexes are also efficient NO scavengers [40, 41].

#### **1.5. Anti-diabetic agents**

Diabetes is the most suffering disease among human beings. This is the disease in which the body do not produce insulin hormone, which is used for absorption of glucose in cells. The control of glucose level is done by vanadium complexes with organic ligands which are less toxic and have improved solubility and lipophilicity [42]. These complexes show involvement in the activation of prominent key components of insulin-signaling pathways [43]. Chromium supplementation also improves glycemia among patients of diabetes [44]. Similarly, higher zinc intake also lowers the risk of type 2 diabetes in women [45].

#### **1.6. Neurological drugs**

Neurological disorders are also treated by transition metal complexes. Lithium is used for Huntington's chorea, tardive dyskinesia, spasmodic torticollis, Tourette's syndrome, L-dopa induced hyperkinesia, Parkinsonism, organic brain disorders, drug induced delusional disorders, migraine and cluster headache, periodic hypersomnolence, epilepsy, Meniere's disease, and periodic hypokalemic paralysis. Lithinium inhibit the scavenging pathways for capturing inositol in the resynthesis of polyphosphoinositides in the brain. Zinc is also used as transmitter in neuronal signaling pathways.

#### **1.7. Delivery probes and diagnostic tools**

Organometallic complexes have unique properties as redox activity, Lewis acidity, electrophilicity, valency, geometry magnetic spectroscopic, and radiochemical properties which can be used to measure cellular functions. Gold nanorods has been used for photoacoustic molecular imaging with simultaneous multiple targeting as they are less reactive and less toxic. The nanoparticles injected in the tumor cells increases their ability to absorb radiation of specific wavelength. The property is used in lymphotropic nanoparticle-enhanced magnetic resonance imaging of prostate cancer. As iron oxide has superparamagnetic properties so they can act as negative contrast agent in magnetic resonance imaging (MRI) which is used to detect the sensitivity of inflamed tissues.

Transition metals exhibit different oxidation states and can interact with several negatively charged molecules. Due to their vital role in medicinal chemistry, we have included both the macro and the nanoorganometallic complexes and their structural and photophysical behavior in detail.

Metallocene compounds have two π-bonded cyclopentadienyl (Cpa) ligands on a metal atom. These compounds are also called "sandwich complexes" due to their symmetrical nature. Other metal complexes with cyclic π-perimeters are also named as metallocenes. Compounds with only one π-perimeter are classified as "half sandwich metallocenes." The bis-cyclopentadienyl complexes are divided in two categories: (a) "classical" with parallel Cp rings and (b) "bent" metallocenes, which have other ligands bonded to the metal in addition to the Cp rings. Ferrocene was the first organometallic compound with antiproliferative properties, so the medicinal properties of the complex were investigated [3]. Ferrocene is nontoxic compound and can be injected, inhaled, or taken orally. It cannot cause major health problems [4, 5]. Another ferrocene-containing compound chloroquine (derivative) is used as antimalarial drug. Ferroquine has an activity-like chloroquine on the malaria parasite *P. falciparum*. The p-methoxybenzyl substituted titanocene show very good activity against renal cell cancer and pleura mesothelioma cell lines. Ruthenium complexes have low toxicity and it has the same mechanism (ligand exchange kinetics) to those of platinum(II) antitumor drugs [10]. A class of ruthenium(II)-arene complexes that are weakly cytotoxic *in vitro*, [Ru(η6-p-arene)Cl<sup>2</sup> (1,3,5-triaza-7-phosphaadamantane)] termed as RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. Dyson et al. recently described the preparation of a series of RAPTA-type complexes with fluoro-substituted η6-arene ligands [46] (**Figure 1**). The active Pt-drug seems to be *cis-*coordinated by bidentate amine ligands or two amines (at least one -NH group on the amine) and two leaving groups with an intermediate binding strength (e.g., Cl− , SO4 2−, citrate or oxalate) to platinum. Nonplatinum metals may have some different chemical behavior (oxidation state, redox potential, coordination geometry, additional coordination sites, binding preferences to biomolecules as the HSAB (hard and soft (Lewis) acids and bases), rate of hydrolysis or kinetics of ligand exchange reactions and the ability to replace essential metals. Due to these differences, the nonplatinum metal-based compounds may have different mechanisms of action, biodistribution, and biological activity.

Studies were carried out on complexes with iron, cobalt or gold, titanium, ruthenium, or gallium central atoms, which have shown the promising results in preclinical studies. Other metal complexes which have shown potential anticancer activity are the complexes of Rh (I), Rh (III) [22, 23, 47], Ir (I), Ir (II), Ir (IV) [48, 20, 21], Os (II), and Os(III) [18, 49–52]. Ferrocifenes [53] exhibit anticancer activity against hormone dependent and hormone-independent breast cancers. Ferrocene derivatives as curcuminoids [54], androgen derivatives [55], and antiandrogens derived from the nilutamide lead structure [56], Theoretical Insight into the Medicinal World of Organometallics: Macro versus Nano http://dx.doi.org/10.5772/67781 7

**Figure 1.** Schematic diagram of few organometallic complexes.

they can act as negative contrast agent in magnetic resonance imaging (MRI) which is used to

Transition metals exhibit different oxidation states and can interact with several negatively charged molecules. Due to their vital role in medicinal chemistry, we have included both the macro and the nanoorganometallic complexes and their structural and photophysical

Metallocene compounds have two π-bonded cyclopentadienyl (Cpa) ligands on a metal atom. These compounds are also called "sandwich complexes" due to their symmetrical nature. Other metal complexes with cyclic π-perimeters are also named as metallocenes. Compounds with only one π-perimeter are classified as "half sandwich metallocenes." The bis-cyclopentadienyl complexes are divided in two categories: (a) "classical" with parallel Cp rings and (b) "bent" metallocenes, which have other ligands bonded to the metal in addition to the Cp rings. Ferrocene was the first organometallic compound with antiproliferative properties, so the medicinal properties of the complex were investigated [3]. Ferrocene is nontoxic compound and can be injected, inhaled, or taken orally. It cannot cause major health problems [4, 5]. Another ferrocene-containing compound chloroquine (derivative) is used as antimalarial drug. Ferroquine has an activity-like chloroquine on the malaria parasite *P. falciparum*. The p-methoxybenzyl substituted titanocene show very good activity against renal cell cancer and pleura mesothelioma cell lines. Ruthenium complexes have low toxicity and it has the same mechanism (ligand exchange kinetics) to those of platinum(II) antitumor drugs [10]. A class of ruthenium(II)-arene complexes that are

as RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. Dyson et al. recently described the preparation of a series of RAPTA-type complexes with fluoro-substituted η6-arene ligands [46] (**Figure 1**). The active Pt-drug seems to be *cis-*coordinated by bidentate amine ligands or two amines (at least one -NH group on the amine) and two leaving groups with an inter-

metals may have some different chemical behavior (oxidation state, redox potential, coordination geometry, additional coordination sites, binding preferences to biomolecules as the HSAB (hard and soft (Lewis) acids and bases), rate of hydrolysis or kinetics of ligand exchange reactions and the ability to replace essential metals. Due to these differences, the nonplatinum metal-based compounds may have different mechanisms of action, biodistri-

Studies were carried out on complexes with iron, cobalt or gold, titanium, ruthenium, or gallium central atoms, which have shown the promising results in preclinical studies. Other metal complexes which have shown potential anticancer activity are the complexes of Rh (I), Rh (III) [22, 23, 47], Ir (I), Ir (II), Ir (IV) [48, 20, 21], Os (II), and Os(III) [18, 49–52]. Ferrocifenes [53] exhibit anticancer activity against hormone dependent and hormone-independent breast cancers. Ferrocene derivatives as curcuminoids [54], androgen derivatives [55], and antiandrogens derived from the nilutamide lead structure [56],

, SO4

(1,3,5-triaza-7-phosphaadamantane)] termed

2−, citrate or oxalate) to platinum. Nonplatinum

detect the sensitivity of inflamed tissues.

6 Recent Progress in Organometallic Chemistry

weakly cytotoxic *in vitro*, [Ru(η6-p-arene)Cl<sup>2</sup>

mediate binding strength (e.g., Cl−

bution, and biological activity.

behavior in detail.

indolones [57], and ferrocenophane polyphenols [58] has also been used for antiproliferative activities.

Transition metal carbene complexes also feature a divalent organic ligand, which is coordinated to the metal center. As these complexes are highly stable and easily derivatize, they can be the suitable candidates for drug development [8, 59].

Metal NHC complexes are also having pharmacological properties as novel antibacterial and antitumor drugs. Their mode of action is both coordinated metal–respective biological target-dependent thioredoxin reductase or other enzymes containing (seleno) cysteine residues in their active site for gold or DNA for copper NHC complexes (half-sandwich) [60, 32], ruthenium [27], or manganese [28, 61] bioorganometallic species and complex containing an acetylsalicylic acid (aspirin) derived ligand emerged as cytotoxic drugs.

An enormous work has been carried out by my mentor Prof. G. Narahari Sastry and group in the field of anticancer treatment. The research group has focused their attention to the biochemical aspects of the clinical application of aromatase inhibitors with designing strategies on toxicity profile, pharmacokinetics, relative potency of aromatase inhibitors, and pharmacophores models [62–73].

As the side effects of these complexes are unavoidable, the research was shifted to the nanotechnology which will have a profound impact on disease prevention, diagnosis, and treatment.

Few advantages of nanotechnology techniques are:

