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However, it is important to note that metal complexes are quickly gaining usefulness
as medicine since they may be tailored like natural products.
4.4.7 Radioactive agents for therapeutic application
Metal-based radioactive agents demand a strategy of complexation of radio metal in a
rapid and high-yielding way. This is done to achieve the objective that, under mild
conditions, the product does not degrade the targeting vector. Commonly used ligand
systems with various metals are DFO (M = Zr(IV) or Ga(III)), DOTA (M = Cu(II), Ga(III),
In(III), Y(III) or Lu(III)), NOTA (M = Cu(II) or Ga(III) and CHX – A″–DTPA (M = In(III) or
Lu(III)).
In addition to these, many MRI contrast agents are also in progress for therapeu-
tic application.
In conclusion, the above sections simply highlight the therapeutic applications of
metals and metal complexes being developed based on their mechanisms of action
[26]. The book focuses on a very wide range of content for metal complexes, so delving
into a deeper understanding and more applications is beyond its scope. The following
section will attempt to provide more details on metal complexes developed for thera-
peutic applications and related topics.
Before we launch into various metal complexes and their therapeutic actions, a
general mechanism for a non-specialist medicinal chemist and chemistry researcher
is a much-needed topic. This would provide an understanding of how drugs actually
act, their causes and paths of action, and the cytotoxicity caused by them [27].
4.4.8 General mechanism of drug action
Be it any route of administering like swallowed, injected, inhaled through the skin,
mucosa under the tongue, mucosa inside the cheek or other routes, drugs mostly
Fig. 4.9: Structure of AEOL.
4.4 Classification of metal-based drugs 61
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enter the blood stream get circulated throughout the body. This is called dynamics.
The drugs then interact with cells or tissues where they produce the desired effect
(this is termed as the target site) . Such interaction is termed as selectivity. Based on
selectivity, drugs can be relatively nonselective, relatively selective and highly selec-
tive. On their surface, most cells have receptors and molecules with a specific three-
dimensional surface that allow only substances that can fit and attach to them (lock-
and-key principle). Hormones and neurotransmitters are such substances. Depending
on the substance, it may stimulate or inhibit a process inside a cell. Some drugs attach
only to a specific type of receptor, while others can attach to several types of receptors
throughout the body. Thus, drugs that target receptors are called agonists or antago-
nists. When they activate or stimulate, they are agonists, and when they block access
or attachment of the body’s natural agonists, they are termed as antagonists. Some
drugs focus on enzymes that regulate the rate of chemical reactions, whereas some
drugs produce effects without changing the function of the cell or attaching to a re-
ceptor. However, the mechanistic part in detail will be discussed with each example
wherever described. The description of metal complexes and their application is con-
densed based on the drug used against a particular disease, and thus they have been
discussed on this basis. The following are the details of diseases or applications of
metal complexes as drugs for each disease.
4.4.9 Anticancer drugs
Most widely applied drugs in chemotherapy are platinum (Pt) drugs, which exhibit
anticancer properties. Three injectable diammine compounds of platinum have been
approved for clinical use.
Since the clinical development of cisplatin, an intensive program for developing SAR
has been gathering impetus . After the mechanism of action of cisplatin was under-
stood, a number of analogous compounds have been clinically applied. Out of 22 new
drugs introduced to clinical trials by the National Cancer Institute (1975–1979), 8 were
analogous to previously tested anticancer agents. Furthermore, the toxicity studies
Pt
NH
3
Cl
NH
3
Cl
Pt
H
3
N
O
H
3
N
O
O
O
cis-platin carboplatin
Fig. 4.10: Structure of cisplatin and carboplatin.
62 Chapter 4 Metal complexes and their therapeutic applications
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and comparison of the toxicity/activity spectrum of cisplatin analogues have been
well documented by groups fr om NCI, Surry and Bristol-Myers [28–32]. A list of
principal second-generation analogues of cisplatin complexes can be briefly men-
tioned here:
(1) CBDCA (diammine (1,1-cyclobutane-dicarboxylato)platinum(II))
(2) CHP ({dis-dichloro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV)
(3) 4-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II)
(4) TNo-6 [(aquo)sulfato(1,1-bis-aminomethyl)cyclohexane)platinum(II)]
(5) MALEN (malano(ethylene diamine)platinum(II))
The structures are shown in Fig. 4.11.
A survey of structures clearly indicates that these complexes are normally NH
3
and
substituted chloride groups, like cyclobutane dicarboxylate, or complexes substituted
on the amine, like 1,2-diaminocyclohexane, as well as Pt(IV) complexes. Although no
trend is observed in their development, nor is any one property or toxicity spectrum
indicative of a general trend, mechanistic understanding leads to the conclusion that
cisplatin and its 1,1-cyclobutanedicarboxylate analog have proved to be clinically ef-
fective for cancer treatment. On the other hand, initial studies on the antibacterial
Pt
NH
2
CHMe
2
Cl
NH
2
CHMe
2
Cl
Pt
H
3
N
O
H
3
N
O
O
O
OH
HO
Pt
N
H
2
O
H
2
N
O
O
O
COOH
Pt
NH
2
OSO
3
NH
2
OH
2
Pt
H
2
N
N
H
2
O
O
O
O
(1)
(2) (3)
(4) (5)
Fig. 4.11: Analogues of cisplatin complexes.
4.4 Classification of metal-based drugs 63
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effect of platinum complexes have also found them to be potential antitumor agents.
Even by manipulating structures, side effects may be reduced. For example, early
dose nephrotoxicity can be mitigated by using sulfur nucleophiles. Further, a number
of such second-generation analogs are undergoing evaluation for their anticancer
properties. Based on these factors, it is also obvious that the mechanism of action of
cytotoxic activity involves DNA binding with subsequent consequences on the ability
to replicate. Futuristic research and a rigorous strategy are the demands of the day.
4.4.10 Metal complexes of other metals for therapeutic applications
Ruthenium and titanium are other metals used for their therapeutic applications.
Fe(II) serum transport protein transferrin can be used to target either blocking iron
uptake or for the release of cytotoxic metal complexes inside cells under pH 5.5 acidic
conditions if the adduct inside cells is labile. Even 67 Ga is known to be transported in
this way in localized tumor tissues. Ga (NO
3
)
3
has been used as an anticancer agent
[33]. It is reported that Ru(II) is also taken up by cells as a transferrin complex. On the
other hand, trans–[RuCl
2
(indazole)
2
] [1nH] is one complex that hydrolyzes at the
same rate as cisplatin. This complex binds to only one of the ligands in the Fe(III)
binding site, without the associated binding of the usual synergistic anion carbonate
[34]. Currently, two Ti(IV) complexes are also in clinical trials, viz. budotitane and tita-
nocene dichloride. These two compounds have a strong tendency toward hydrolysis,
which is a challenge for their formulation before administration.
4.4.11 Gold antiarthritic drugs
Myocrisin
®
, aurothioglucose (Solganol
®
) and aurothiopropanol sulfonate (Allochrysin
®
)
are some injectable Au(I) thiolates that are widely used for the treatment of difficult
cases of rheumatoid arthritis [35]. It is mechanistically understood that Au(I) has a
much higher affinity for S compounds (thiolates) compared to thioethers and very low
affinity for N and O ligands. This, therefore, implies that Au(I) binds to DNA very
weakly and thus is not usually carcinogenic or mutagenic. It is further observed in
the thiolate excha nge reaction that the administered drugs are probably not active
pharmacologically.
4.4.12 Antitumor activity of metal complexes
Owing to the demonstration of antitumor activity of cisplatin, many other transition
metal complexes have been screened and found active for antitumor activities. How-
ever, few systematic studies have been done. Although intensive screening by the Na-
64 Chapter 4 Metal complexes and their therapeutic applications
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tional Cancer Institute Screening Program yielded a total of 14,000 compounds of inor-
ganic nature, of which 8,000 were metal complexes [36–38], systematic studies have
been carried out on a number of amines, cyclopentadenyls and macrocycles due to their
similarities with platinum complexes. Since 1987, non-platinum metal complexes have
not been used for full clinical trials, but they are promising candidates. Examples include
palladium, rhodium and ruthenium complexes. Even some of the copper complexes
based on anions such as semicarbazone and 1,10-phenanthroline, and other oxygen and
nitrogen ligands are being explored for antitumor activity.
4.4.13 Therapeutic application of metal-based as antimicrobial agents
There is no doubt about the role of coordination compounds in medicinal applica-
tions. Although they have played a very important role in medicine, they are paid less
attention. In recent years, there have been many studies that demonstrate that the
levelofmicroorganismsthatresistmultiple drugs is continuously increasing [39].
Metal-based drugs can thus provide a solution to this problem and replace many or-
ganic molecules conventionally employed for treatment. The fact that complexation
produces a synergistic effect is the factor that enhances their application as drugs, as
this improves the bioavailability of the drug and thus helps in efficacy. An example is
the bismuth-norfloxacin complex, which shows better antimicrobial activity [40].
Studies have further shown that the activity of the strongest antibiotics has reduced
drastically against a number of microbes, e.g., microfungi and bacteria. Metal com-
plexes and their application in drugs have definitely opened up a new possibility. A
WHO report on the surveillance of antibiotic consumption (2016–2018) mentions that
“The overall consumption of antibiotics ranged from 44 to 64.4 defined daily doses
(DDD) per 1,000 inhabitants per day.” On the other hand, the rate of development of
new antibiotics is far behind the rate of emergence of antibiotic resistance. Conclu-
sively, the development of new antibiotics is the biggest challenge for health manage-
ment personnel [41]. Looking at the importance of antimicrobial agents based on
metal complexes, a review [42] discusses and highlights various aspects of this class of
metal complexes used. Not only this, but there has also been an interest in metals as
antimicrobial and biocidal agents, with the hope that less resistance will evolve for
these compounds. Since this chapter is entirely dedicated to metal complexes as me-
dicinal compounds/drugs, a list of complexes/compounds is given before discussing
these in detail:
A. Silver and its compounds
B. Copper and its compounds
C. Zinc and its compounds
D. Iron and its compounds
E. Ruthenium and its compound
F. Gold and its components
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G. Molybdenum and its components
H. Gallium and its compounds
I. Indium and its compounds
J. Aluminum and its compounds
K. Miscellaneous
4.4.13.1 Silver and its compounds
Historically, silver and its compounds have been used as antimicrobial agents since
ancient times [43–46]. Silver sulfadiazine (Ag SD) is one such example whose antimi-
crobial activity has been described by several authors [47–49] (Fig. 4.12).
Other silver complexes show cytotoxic effects against gram-positive/gram-negative
bacteria and f ungi, though the exact mechanism of action of silver, other than its
strong affinity to react with sulfhydryl (SH) groups in the bacterial cell, is not fully
known. It has been shown that silver induces structural changes in bacterial cells and
interacts with nucleic acids [50, 51]. This kind of interaction denatures proteins, which
causes impairment of membrane functions [52, 53]. Silver ions can even produce ROS,
which often target lipids, DNA, RNA, and proteins, causing malfunctioning of mem-
branes, proteins and DNA replication mechanisms [54, 55].
A number of new compounds, e.g., N-heterocyclic carbene (NHC) complexes, N-
heterocyclic complexes and phosphine complexes of silver(I), have been found to be
antimicrobial [56]. The structure of one such complex is depicted in Fig. 4.13,and it
has been mentioned that NHC ligands form stable complexes with silver that help
modulate the release of silver to facilitate its systemic delivery. A number of such
complexes have shown antibacterial activity against Escherichia coli (E. coli), Staphy-
lococcus aureus and Pseudomonas aeruginosa. The tentative mechanism is through in-
tercalation with DNA or disrupting the cell membrane [57].
The activity of silver complexes, namely tetrazole-containing 1-benzyl-1H-tetrazole
(BNTZ), 1-benzyl-1-H tetrazol-5-amine (BNTZA) and 1-{4-methoxybenzyl}-1-H-5-amine
(MBNTZA), has suggested that these complexes exhib it s ignificant activit y ag ainst a
broad panel of gram-positive and gram-negative bacteria as well as fungi. Their MIC
values are in the range of 2–8 and 0.16–1.25 µg/mL, respectively. This has been further
validated, showing that the activities are due to the presence of Ag(I) ions [58, 59]. Cam-
phoramine complexes of Ag(O) or Ag(Cl) demonstrate good activity against Candida spe-
H
2
N
S
O
O
N
Ag
Fig. 4.12: Silver sulfadiazine.
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cies, with oxo and hydroxo silver camphoramine complexes exhibiting higher antifun-
gal activity against C. albicans and C. glabrata [60].
Silver nanoparticles (SNPs) have also been widely used in medicinal applications
[61]. Reports of SNPs synthesized from bark extracts of Boswellia and Shorea tumbug-
gara show toxic activity against Klebsiella and Aspergillus as well as Pseudomonas and
Fusarium. Even E. coli inhibition rates have been shown to have a proportional rela-
tionship with the concentration of Ag NP [62]. The antibacterial activity of Ag NP is size-
dependent since small-sized Ag NP has shown interaction with the cell wall [63].
4.4.13.2 Copper and its compounds
Organisms need copper as an essential element for a number of functions, yet it can
be toxic in large concentrations [64].
Fundamentally, a number of copper-containing proteins are present in microbes,
and copper acts as an electron donor/acceptor due to its ability to switch between
Cu(I) and Cu(II) ions [65]. A number of researchers have studied coordination com-
pounds of copper and recommended that the antimicrobial activity of such com-
pounds is improved by complexing. The nature of the ligand and geometry of such
complexes decide the mechanism of their action [65, 66]. However, the exact mecha-
nism of the antimicrobial activity of copper is not known. It has been investigated by
a number of studies that the Fenton-type reaction produces ROS, which damage DNA,
and the release of copper ions causes inactivation of enzymes leading to toxicity [67].
Figure 4.14 shows some copper complexes having antimicrobial properties.
N
N
Ag
Ag
N
HO
OH
R
R
2-3 2-3
OH
Fig. 4.13: Ag NHC complex (Youngs et al.).
4.4 Classification of metal-based drugs 67
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There has been use of copper nanoparticles for their antimicrobial application. The
activities have been reported against Micrococcus luteus, Staphylococcus aureus, Es-
cherichia coli, Klebsiella pneumoniae, as well as Pseudomonas aeruginosa, including
fungi such as Aspergillus flavus, Aspergillus niger and Candida albicans. The reports
show that copper nanoparticles have better antibacterial activity compared to anti-
fungal activity [68].
4.4.13.3 Zinc and its compounds
Zinc is an important element in biological systems, and as Zn
2+
ions, it plays a vital
role as a metalloenzyme Fig 4.15. It is thought to be nontoxic if administered orally.
Zn plays an important role in metal-based pharmaceuticals [69–71]. The mechanism
of action of zinc complexes is through two modes:
(1) By direct action, the microbial membrane is destabilized, thereby increasing its
permeability.
(2) By indirect action, complexes interact with nucleic acids and deactivate respira-
tory enzymes [70]. A summary of Zn complexes, along with their activity, is in-
cluded in Tab 4.1.
4.4.13.4 Iron and its compounds
Since iron is vital in the growth of pathogenic bacteria, its complexes with organic mol-
ecules showing antibacterial/antimicrobial activity are of significant importance [75].
Iron is thus a carrier for the antimicrobial molecules. Such metal antibiotics synthesized
using schemes to enhance efficiency are of prime application. Using this strategy, iron-
quinoxaline derivatives have been developed to help enhance the antibacterial activity
of quinoxaline derivatives to cure tuberculosis. As compared to the free ligand, the com-
pounds have been found to possess higher activity against Mycobacterium tuberculosis
Fig. 4.14: Copper complexes with antimicrobial properties.
68 Chapter 4 Metal complexes and their therapeutic applications
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[76, 77]. The mechanistic approach for such enhancement of activity for iron complexes
is that iron(III) efficiently carries bioactive ligands and increases their concentration in-
side the target microbial cells. Iron(III) complexes of 1,2,4-triazole Schiff bases also have
been reported to exhibit greater antimicrobial action compared to free ligands [78]. It
has been understood that chelation helps in increasing the bioactivity of a given com-
plex since it enhances the lipophilicity of the central metal. This further facilitates pass-
Fig. 4.15: Structure of various Zn(II) complexes.
Tab. 4.1: Various complexes of Zn(II) and their activities.
S. no. Zn compound/complex Activity against References
. Zn(II) complexes vs. fluconazole Candida albicans
Aspergillus niger (– times higher)
[]
. Zn complexes of Schiff base ligands Bacteriostatic and bactericidal properties []
. Zn complexes with ibuprofen
(Geometry-dependent activities)
Micrococcus luteus, Staphylococcus aureus,
Bacillus subtilis, E. coli, K. pneumoniae and
Proteus mirabilis
[]
. Zn(II) complexes of cycling Anti-HIV activity []
4.4 Classification of metal-based drugs 69
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ing through the microbial membrane. Conclusively, there is potential in designing
drugs using this strategy with higher activity compared to the parent organic molecule.
4.4.13.5 Ruthenium and its compounds
Ruthenium and some of its complexes have been shown to have potent antimicrobial
activity. Such compounds include octahedral ruthenium(II ) complexes, which show
antimicrobial activity against Mycobacterium smegmatis [79].Further,ithasbeen
found that dinuclear Ru(II) complexes linked by long alkyl chains show measurable
inhibitory activity against gram-positive as well as gram-negative bacteria. The com-
plexes are depicted in Fig. 4.16. Even the curcumin complexes of ruthenium(II) poly-
pyridyl show good activity against drug-resistant S. aureus ATCC [80].
4.4.13.6 Gold and its compounds
Apart from its application for treating syphilis, tuberculosis and inflammatory rheu-
matoid arthritis, it has antimicrobial properties too. The following derivatives of gold
have been used and found application as antimicrobials:
(i) Gold(I) alkynyl chromone complexes have been found to have high levels of activity
against methicillin-sensitive (MSSA) and methicillin-resistant S. aureus (MRSA).
(ii) Auranofin has been reported to have significant activity against gram-positive
bacteria including multidrug-resistant bacteria as well as M. tuberculosis.
(iii) Gold(I) bis-NHC complexes have shown activity against MRSA.
N
N
N
N
N
N
Ru
N
N
N
N
N
N
Ru
n
3+ 3+
Fig. 4.16: Structure of various ruthenium complexes.
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