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1.1 General introduction on coordination chemistry
Coordination chemistry is one of the most active research fields in chemistry
today, though it has got a history of a century. During the nineteenth century coordination
compounds attracted attention due to their tremendous importance to the general problem
of chemical bonding as also for their own unique and fascinating properties.
Alfred Werner was the founder of coordination chemistry. His most famous paper
titled “Contribution of inorganic compounds” [1] marked the beginning of modern
coordination chemistry. Werner’s coordination theory has been a guiding principle in
inorganic chemistry [2, 3]. His theory not only gave insight into sterochemical aspects,
but also stimulated for synthesis of varieties of coordination compounds.
A hundred years after the formulation of the coordination theory, stereo chemical
considerations are again at the centre of interest in the development of metal complexes
[4]. Coordination chemistry naturally centers on the synthesis of coordination
compounds, the synthesis of these materials is typically not an end in itself. Coordination
C o
n t
e n
t s
1.1 General introduction on coordination chemistry 1
1.2 Coordination compounds in nature 2
1.3 Coordination compounds in medicinal chemistry 5
1.4 Coordination compounds in the industry 8
1.5 Coordination compounds as antimicrobial agents 10
1.6 Coordination compounds as antioxidant agents 11
1.7 Coordination compounds as xanthine oxidase inhibitory agents 12
1.8 Coordination compounds as anticancer agents 13
1.9 Macrocyclic and azamacrocyclic compounds 16
1.10 Aims and objectives 20
1.11 Reference 21
1
Chapter
General Introduction on
Coordination Chemistry
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compounds are utilized in all branches of chemistry, from theoretical modeling to
industrial and consumer products [5].
The diversity of modern coordination chemistry today and the evolution of
coordination chemistry into a link between different fields of modern chemistry were
impressively demonstrated. Bioinorganic chemistry may be molecular precursors for
novel materials, supramolecular chemistry; of homogeneous metal catalysis coordination
units constitute the fundamental building blocks [6]. Coordination chemistry has
registered a significant growth during the last few decades [7]. This branch of chemistry
has undergone lots of changes with greater understanding of the nature of the chemical
bond and structure of coordination complexes [8].
The conceptual base of structure and bonding in coordination chemistry has
evolved from simple Lewis acid-base ideas and hard and soft acids and bases,
sequentially, through valence bond theory, crystal field theory, ligand filed theory, the
angular overlap model, and onward through a diversity of molecular orbital models,
Study of the reactions of coordination compounds has been manifested in magnificent
contribution to the understanding of their mechanisms. The great variety in properties of
the bonds around metals is the beauty of coordination chemistry.
1.2. Coordination compounds in nature
Naturally occurring coordination compounds are vital to living organisms. Metal
complexes play important and diversified roles in biological systems. Many enzymes, the
naturally occurring catalysts that regulate biological processes, are metal complexes
(metalloenzymes); for example, carboxypeptidase (Fig: 1.1), a hydrolytic enzyme
important in digestion, contains a zinc ion coordinated to several amino acid residues of
the protein. Another enzyme, catalase (Fig: 1.2), which is an efficient catalyst for the
decomposition of hydrogen peroxide, contains iron-porphyrin complexes. In both cases,
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the coordinated metal ions are probably the sites of catalytic activity. Other biologically
important coordination compounds include, for example, the pigment responsible for
photosynthesis chlorophyll is a coordinated compound of magnesium (Fig:1.3),
Haemoglobin, the red pigment of blood also contains iron-porphyrin complexes (Fig:1.4),
its role as an oxygen carrier being related to the ability of the iron atoms to coordinate
oxygen molecules reversibly, vitamin B12 is coordination compounds of cobalt (Fig:1.5)
and hemocyanin (Fig:1.6) of invertebrate animal blood is a coordination compound of
copper and carbonic anhydrases (Fig:1.7) are zinc-containing enzymes that catalyze the
reversible reaction between carbon dioxide hydration and bicarbonate dehydration. Above
points illustrate the intimate linkage between inorganic chemistry and biology.
R
O O
NH R'
O
Zn2+
O
H
HO
GluO
R
O O
NH R'
O
Zn2+
O
H
HO
GluO
Enzyme substrate complexTetrahedral intermediate
Figure: 1.1
N N
N N
H3C
CH3
CH3
CH2CH2COOH
CH2CH2COOH
H3C
H2C=HC
CH=CH2
Fe
Haemin
Figure: 1.2
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N N
N N
H3C
R
CH3
H2C
H2C=HC
C2H5
Mg
H3C
H
CH2
OH
H
COOCH3
COOC20H39
H3C
N
CH
N
CH3
HC
N
H3CCH
N
CH3
CH
COOHCOOH
CH2
CH2
Fe
R= CH3 it is chlorophyll-aR= CHO it is chlorophyll-b
Figure: 1.3 Figure: 1.4
H
HHOCH3
O OH
H HO
3'
N
N
CH3
CH3
P
OO
O
CH
CH2
HN
CH2C CH2
CH3
O
CH3
N
CH3
CH2
C
H2N
O
Co
N
CH3
CH3
CH2
H2C
C
H2N
CH2
C
NH2
OO
CH3
N H2C
CH3
C NH2
CH2
H2C C NH2
O
OOH
N
CH3
CH3H2CCH2
C NH2
O
Cobalamin (Vitamin B12)
Corrin ring system
5,6-di-methylbenzimidazole ribonucleotide
N
N
NH
N
NH
NH
Cu(i)
N N
N
NH
Cu(i)
NHNH
HN
N
NH
NH
N
NH
N
NN
N
NH
Cu(II)
O
O
Cu(II)
O2
Figure: 1.5 Figure: 1.6
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O
HH
Zn2+
HisHis
His
H+
O
H
Zn2+
HisHis
His
-
CO2
O
H
Zn2+
HisHis
His
- C
O
O
O
CH
Zn2+
HisHis
His
O
O-
HCO3-
H2O
1
2
3
4
Figure: 1.7
1.3. Coordination compounds in medicinal chemistry
Coordination complexes have a long history of use as chemotherapeutic agents.
The use of inorganic substance in medicine has its origin from the time of hippocrates. He
recommended the medicinal use of metallic salts. However, the logical bases for
understanding the role of inorganic species in medicine have been established only after
the advances in the field of bio-inorganic chemistry.
The successful applications of inorganic complexes as drugs, it involves the
recognition of their bioinorganic modes of action coupled with the traditional
pharmacokinetic parameters. Further, the rational approaches to chemotherapy and
particularly the notion of selective toxicity [9, 10] must be placed in an inorganic context.
The concept of selective toxicity and its scientific basis, is of particular use in describing
the actions of drugs on an invading organism, be it viral, bacterial, parasitic or ultimately
malignant tumours caused by the cancerous growth of the host’s cells. The achievement
of some form of selectivity is critical to the successful use of any agent as a drug or
modifier of biological response.
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During the later part of the 20th century, pharmaceutical compounds containing
metals began to play an increasingly important role in medicine [11]. In particular, the
discovery of platinum anticancer drugs(Fig:1.8) and the appearance of organ specific
diagnostic-imaging agents containing technetium were prominent developments that have
stimulated further interest in so called ‘metallo-pharmaceuticals’. Today, the metallo-
pharmaceutical industry has a global market, measured in billions of pounds and has well-
established applications in both diagnostic and therapeutic medicine.
ClPt
NH3
Cl NH3
Cisplatin
ClPt
NH3
NH3 Cl
Transplatin
NH2
Pt
NH2
O
O O
OOxaliplatin
NH
NH
Pt
Cl
ClCl
Cl
Tetraplatin
NH Pt4+
O--Cl
H2N
Cl-
O-
CH3
CH3
O
O
Satraplatin
PtO
O
NH3
NH3
O
OCarboplatin
NPt
NH3 Ci
Cl
CH3Picoplatin
H 3 C
HN+ Pt 4CH 3
O -
Cl -
Cl --O
HN
CH 3
CH 3Ip r o p la t in
Figure: 1.8
Current medical practice has access to a variety of metals containing
pharmaceuticals. In addition to the continued use of gold drugs to treat rheumatoid
arthritis [12-14], lithium is now used to treat depression, platinum to treat certain types of
cancer [15], bismuth to treat stomach ulcers [16, 17], vanadium to treat some cases of
diabetes [18, 19], iron to treat anemia [20], iron compounds to control blood pressure,
cobalt in vitamin B12 to treat pernicious anemia and certain radioactive metals to alleviate
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the pain of bone cancer. Beyond these therapeutic uses metals have also become
important in diagnostic medicine, particularly diagnostic imaging applications. In
addition to technetium, radioactive forms of thallium, gallium and indium are also used
routinely for diagnostic imaging purposes [21, 22]. Another important diagnostic imaging
technique developed more recently, uses as magnetic resonance to produce images of
internal organs by examining the water content of the tissues involved. Metals with
magnetic properties, particularly gadolinium, are finding use as a means of enhancing
some of the images produced by this method. Complexes containing gadolinium, cobalt,
lithium, bismuth, iron, calcium, lanthanum, gallium, tin, arsenic, rhodium, copper, zinc,
aluminum and lutetium have all been used in medicine [23].
Bacterial, viral and malignant tumors (cancer) remain the most life threatening,
refractory and global killer diseases around the world. Present therapy involving organic
moieties as therapeutic agents is increasingly getting marginalized due to the rapid
emergence of drug resistance, limited target specificity and difficult to achieve
therapeutic drug levels.
Consequently metallo drugs offer unique advantages in overcoming these
difficulties. These are the compounds incorporating biologically relevant transition metal
ions and integral part of their structural scaffold and possess clinical and therapeutic
value. They can provide synergized bioavailability through increased liposolubility,
enhanced biological activity and selective targeting of certain proteins/ receptors and
activity against drug-resistant species.
The predominant role of DNA in cellular replication and transmission of genetic
information makes the nucleic acids a primary target for drug action, and many drugs are
considered to act fundamentally at this level. In the case of metals (metal-aqua
complexes) and other metal complexes, the subject of their interaction with DNA is
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relevant for a number of reasons. These systems range from in vivo aspect, such as the
endogenous presence in the nucleus of metal ions, the role of zinc in RNA polymerase,
the mutagenesis and eventual carcinogenesis of metal ions, the diverse uses of metal ions
as probes of polynucleotide structure, as well as the cytotoxic effects of metal-complexes.
Transition metal complexes cleaving DNA under physiological conditions are of
considerable current interests for their various applications in nucleic acids chemistry.
The nuclease activity can be targeted to one of the linkages/constituents of DNA. Among
different modes of DNA cleavage, oxidative cleavage of DNA on irradiation of light has
gained current interests due to its utility in photodynamic therapy of cancer. While
porphyrin and related compounds have been extensively used to study the cleavage of
DNA on photo-exposure, current efforts are on to design transition metal based
coordination complexes as new DNA cleaving agents.
There has been an increasing interest in the synthesis of novel model metal
coordination compounds to mimic biological reactions. These investigations constitute
one of the major lines of pursuit in bioinorganic chemistry concept. These model studies
have been useful to understand the role of metal ions in specified coordination geometries
dictating the course and nature of reaction in biological systems. One of the successful
routes to tackle this problem is through the investigations on structure-property
correlation of new complexes. It is, therefore, worthwhile to study on the synthesis of
some biologically active ligands and their metal complexes.
1.4. Coordination compounds in the industry
The applications of coordination compounds in chemistry and technology are
many and varied. The brilliant and intense colors of many coordination compounds, such
as Prussian blue, render them of great value as dyes and
pigments. Phthalocyanine complexes (Fig: 1.9), containing large-ring ligands closely
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related to the porphyrins, constitute an important class of dyes for fabrics. Several
important hydrometallurgical processes utilize metal complexes. Cyanide complexes also
find application in electroplating. There are a number of ways in which coordination
compounds are used in the analysis of various substances like selective precipitation of
metal ions as complexes, for example, nickel(II) ion as the dimethylglyoxime complex
(Fig:1.10).
N
N
N
N
N
N
N
NCu
H3CC
CH3C N
N
O
O
H
O
H
O
N
N
NiC
C
CH3
CH3
Figure: 1.9 Figure: 1.10
Since 1940 there has been an upsurge of research in the area of catalysis by
transition metal complexes. In 1954, a technological and scientific development of major
significance was the discoved that certain metal complex acts as catalysts. The demand
for cheaper and more efficient processes in the industry necessitated a major explosion of
research in the area of synthetic chemistry to develop new system that can act as catalysts.
This also resulted in a rapid development of newer process technologies relevant to
industrial scale reactions for the production of organic compounds using transition metal
complexes as catalysts. A great number of soluble metal complexes are now being
employed in industry as catalysts for the generation of a variety of useful compounds.
Hence, in industries coordination chemistry has sustained interest in catalysis [24-
30], radiopharmacy [31], photography, high technology industries such as electronics
[32], dyeing [33-35], metallurgy [36-37], metal ion sequestration, solvent extraction,
leather tanning, electroplating, water softening and many other industrial processes.
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1.5. Coordination compounds as antimicrobial agents
Infectious diseases is a major problem in the progress in human medicine and
their control remains a huge challenge since vaccines are only available against a limited
number of pathogens. Bacteria are extremely pathogenic, causing infection and
widespread use of commercially available antibiotics led to the developed resistance or
ability to produce substance which block the action of antibiotics or change their target
and produce undesirable side effects [38]. Although, a number of different classes of
antibacterial and antifungal agents have been discovered during the last two decades the
use is limited due to the development of microbial resistance [39].
Most of the current anti-infective suffers from considerable limitations in terms of
antimicrobial spectrum and side-effects, and their widespread overuse has led to drug
resistance [40]. The use of most antimicrobial agents is limited, not only by the rapidly
developing drug resistance, but also by the unsatisfactory status of the present treatment
of bacterial and fungal infections [41-43].
Resistance to a number of antimicrobial agents (b-lactam antibiotics, macrolides,
quinolones, and vancomycin) among a variety of clinically significant species of bacteria
is becoming an increasingly important global problem. Also a number of recent clinical
reports describe the increasing occurrence of methicillin resistant Staphylococcus Aureus
(MRSA) which is most disturbing cause of nosocomial infections in developed countries
[44, 45]. Infections caused by these microorganisms pose a serious challenge to the
medical community and the need for an effective therapy has led to a search for novel
antimicrobial agents. Any subtle change in the drug molecule, which may not be detected
by chemical methods, can be revealed by a change in the antimicrobial activity.
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The significance of macrocyclic compounds has been explored for their
antibacterial activity [46-48]. Several mono and binuclear transition metal complexes of
the Schiff base are more potent bactericides and fungicides than the ligand [49].
Zinc(II) complexes appeared to have good antibacterial activity [50]. Various nitrogen-
donor ligands have been studied and the complexes were found more potent than the
drugs alone [51].
1.6. Coordination compounds as antioxidant agents
Damage to cells caused by free radicals is believed to play a central role in the
aging process and in disease progression. Antioxidants are our first line of defense against
free radical damage, and are critical for maintaining optimum health and wellbeing.
Ascorbic acid (Vitamin C), alpha-tocopherol (Vitamin E), beta-carotene and enzymes
such as catalase, superoxide dismutase (SOD) and glutathione peroxidase are some of the
well-known antioxidants. The need for antioxidants becomes even more critical with
increased exposure to free radicals [52]. Pollution, cigarette smoke, drugs, illness, stress,
and even exercise can increase free radical exposure.
Antioxidants are very helpful in prevention of diseases in human being [53].
Antioxidant compounds which play an important role in food and chemical material
degradation, and significantly delay or prevent the oxidation of easily oxidable substrates.
Hence, need for the good antioxidants have greatly increased in the recent years [54,55].
Transition metal complexes have notably shown important antioxidant properties,
viz SOD mimetic activity [56]. The macrocyclic nature of the ligand seems important for
the SOD mimetic activity of the corresponding complexes as well as for their stability in
the presence of proteins, even if the metal ion does not lie inside the cavity [57].
Copper(II) complexes can enclose a SOD mimetic activity hindering increased levels of
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reactive oxygen species [58]. Several macrocyclic copper complexes have been reported
to scavenge the superoxide anion [59-62].
1.7. Coordination compounds as xanthine oxidase inhibitory agents
Xanthine oxidase (XO), a molybdoflavo protein, is a key enzyme in purine
metabolism that has been isolated from a wide range of organisms, including bacteria and
humans [63, 64]. The XO catalyzes the hydroxylation of hypoxanthine and xanthine to
yield uric acid and hydrogen peroxides. The enzyme is responsible for the medical
condition known as gout. Gout is caused by high uric acid (hyperuricemia) in the blood
that leads to excess uric acid crystallizing in the joints leading to swelling and painful
inflammation [65]. This is either caused by the overproduction of uric acid or under
excretion by the kidneys. Uric acid is produced from the breakdown of the purine which
is released when cells die or introduced from the food we eat. Under normal conditions,
uric acid is supposedly produced in enough quantities so as to be efficiently removed by
fully-functioning kidneys. There are cases, however, when specific enzyme defects cause
excessive production of uric acid. The enzyme that helps in breakdown of purine to uric
acid is XO. Since XO makes the conversion of purine into uric acid happen, preventing
its activity results to slow down of uric acid production. Such is the role of xanthine
oxidase inhibitors (XOI) (Figure: 1.17).
It has attracted lots of attention because of its potential role in tissue and vascular
injuries, as well as in inflammatory diseases and chronic heart failure [66, 67]. The
production of reactive oxygen species (ROS) by XO and its damaging consequences has
prompted investigations into the ability of some compounds to control and/or inhibit the
enzyme activity or to scavenge the free radicals produced [68, 69]. Allopurinol (1, 5-
dihydro-4Hpyrazolo [3, 4-d] pyrimidin-4-one), a purine analogue was the first XO
inhibitor approved by the FDA in 1966 and has been the cornerstone of the clinical
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management of gout and conditions associated with hyperuricemia for several decades
[66]. However, due to lack of free radical scavenging activity against superoxide anions
produced, use of allopurinol is associated with some side effects that include allergy,
hypersensitivity reactions, gastrointestinal upset, skin rashes and acute interstitial
nephritis [67]. Hence, novel compounds with better safety profiles should prepare that
could be used to relieve associated side effects.
Alterations in XO activity of various metals have also been probed with mixed
results of either stimulation or inhibition, depending on the metal [70]. As mentioned
above, because of its ubiquity and its ability to bind to proteins, copper would be one of
the metals to probe in priority. However, although partial inhibition of XO activity by
Cu2+ has been reported [71] there is no thorough investigation on the effect of the metal
on the enzyme activity and structure, nor on the potential attachment sites for the metal.
HN
N NH
N
O
HN
N NH
N
O
O
HN
N
N
O
NH
NH
NH
N
O
O
HN
NH
NH
NH
O
O
O
inhibits xanthineoxidase
xanthineoxidase
alloxanthine-anon-compotitive xanthineoxidase inhibitor xanthine
blocks uric acid production
allopurinol - blocks theaction of xanthine oxidase
by substrate competition and us also metabolised b it to form alloxanthine
xanthineoxidase
xanthineoxidase
nypoxanthine - a breakedownproduct of adenine - catalysed
by adenase (EC 3,5,4,2)
uric acid - relatively insoluble compoundwhich can build up in joints leading to its
crystallization and painful and inflamed joints (gout)
xanthine
×
× ×
×
Figure: 1.17
1.8. Coordination compounds as anticancer agents
The medical term for cancer is neoplasm, which means “a relatively autonomous
growth of tissues” [72]. It is a collective term for a group of diseases characterized by the
loss of control of the growth, division and spread of a group of cells. It can form an
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encapsulated benign tumor, leading to invasion and destruction of adjacent tissues. On the
other hand, non encapsulated malignant tumors grow rapidly, and can spread to various
regions of the body and metastasize.
Since the discovery of the anti-cancer activity of cisplatin, some 40 years ago,
there has been a growing interest in the field of metal complex-based chemotherapy. In
addition to platinum, medicinal chemists have investigated complexes with other
transition metals such as ruthenium, copper, cobalt, palladium and gold as a way of
killing cancer cells. This has given rise to the field of metal-based anticancer agents, a
discipline that is very rapidly expanded and brought about the discovery of many
interesting and effective anticancer agents.
Before the great success of cisplatin, the idea of using inorganic chemicals to treat
cancer was rather uncommon. Heavy metals, causing cases of poisoning, were not
assumed to act as potential anticancer drugs because of their toxicity. The earliest attempt
to introduce metals in the drug development was so called Fowler´s solution, giving rise
of arsenotherapy [73]. Some of similar compounds are still being used today, such as
As2O3 [74]. Metal ion complexes very quickly turned out to be interesting and attractive
compounds in the development of anticancer drugs because of their chemical reactivity.
In addition, the possibility of many different coordination geometries enables the
synthesis of compounds with stereochemistry that are quite unique and not obtainable in
the group of pure organic compounds [75].
Development of new therapeutic modalities for cancer chemotherapy is the
subject of immense interest owing to the fact that many present treatment regimes in
chemotherapy have failed or fall short either in terms of efficiency or toxicity problems
associated with them [76-78]. Among the non platinum complexes for metal based
chemotherapy, copper and zinc complexes have been much explored due to the fact that
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both copper and zinc are bioessential elements responsible for numerous bioactivities in
living organism [79]. Zinc is the second prominent trace metal in the human body which
is critical for numerous cell processes and is major regulatory ion in the metabolism of
cells [80].
DNA is an important drug target that regulates many biochemical processes that
occur in the cellular system. The different loci present in the DNA are involved in
various regulatory processes such as carcinogenesis, mutageneis, gene transcription, gene
expression, etc [81]. Many small molecules exert their anticancer activities by binding
with DNA, thereby altering DNA replication and inhibiting the growth of tumor cells.
Small metal complexes that undergo hydrolytic DNA cleavage are useful in genetic
engineering, molecular biotechnology and robust anticancer drug design [82, 83].
Angiogenesis is a feature of embryonic development and in several physiological
and pathological conditions, including rheumatoid arthritis, psoriasis, tumor growth and
metastasis, diabetic retinopathy and age-related macular degeneration [84]. It appears to
depend on the balance of several stimulating and inhibiting factors [85]. Angiogenesis-
dependent diseases are controlled by using chemotherapy, immunotherapy and radiation
therapy to inhibit the stimulating or stimulate the inhibiting factors. Anti-angiogenesis,
i.e. inhibition of blood vessel growth, as a way of treating primary tumors and reducing
their metastases, was first proposed by Judah Folkman in 1971 [86].
The design of Schiff-base complexes has received long-lasting research interest
not only because of their appealing structural and topological novelty, but also due to
their potential medicinal value derived from their antiviral and the inhibition of
angiogenesis [87, 88].
Recently, more than a thousand potential anticancer metal compounds, from the
National Cancer Institute (NCI) tumor-screening database, were analyzed based on
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putative mechanisms of action, and classified into four broad classes, according to their
preference for binding to sulfhydryl groups, chelation, generation of reactive oxygen
species, and production of lipophilic ions [89]. Additionally, increasing knowledge of the
biological activities of simple metal complexes guided many researchers in the
development of promising chemotherapeutic compounds which target specific
physiological or pathological processes. Many potential antitumoral agents have been
investigated based on their anti-angiogenesis or pro-apoptotic behaviour. These studies
involve both designed and natural products, in association with essential metal ions such
as copper, or iron [90-92].
1.9. Macrocyclic and azamacrocyclic compounds
Macrocyclic chemistry is a field of coordination chemistry that has thrown light
on a vast number of interesting and important naturally occurring and synthesized
macrocycles and their complexes [93-95]. It is a very active and rapidly growing field of
research that overlaps with some interesting fields of chemistry such as catalytic
chemistry, metalloenzymes [96], biomimetic chemistry[97,98] and supramolecular
chemistry to which a number of scientists have been attracted. The significance of the
subject matter of macrocyclic chemistry extends from a large number of life composing
and naturally occurring complexes with enormous biological functions and non-biological
functions [99, 100]. The chemistry of macrcocyles and its complexes have attracted the
interest of both inorganic and bioinorganic chemists in recent years [101-105] due to their
unique structural properties [106] and biological activities [107].
Basically, macrocycles or macrocyclic ligands in inorganic chemistry usually refer
to nine membered or greater ring containing organic molecules, usually with twelve or
more atoms in which three or more hetero-atom donors such as N, O, S, P, etc. binding
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sites have been interspersed [108]. The following structures are some examples of
azamacrocycles (Fig: 1.11-1.13).
HN HN
NH
N N
N N
Me
Me
NH
NH
HN
HN
NH
NH
HN
HN
Figure: 1.11 Figure: 1.12 Figure: 1.13
Polyazamacrocycles containing amide groups (Fig: 1.14-1.16) possess two possible
potential donor atoms (N and O) and hence deserve special interest.
N NH NH
NH NNH
CH3
O
M M
NH NH
NNH
CH3
O
M
X
X
Figure: 1.14 Figure: 1.15
HN
HN
HN
NH
O
O
O
O
n
m
Figure: 1.16
Macrocyclic ligands have attracted widespread attention due to two unique
properties (a) their ability to discriminate among closely related metal ions based on the
metal ion radius (ring size effect). (b) The significant enhancement in complex stability
constants which is generally exhibited by optimally-fitting macrocyclic ligands relative to
their open chain analogues (macrocyclic effect). For a number of systems in which the
metal ion fully occupies the macrocyclic cavity, there is tendency for maximum stability
to occur in the ligand for which the cavity size best matches the radius of ions.
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Complexation with such macrocycles has stimulated a number of scientists to synthesize
and investigate many macrocycles for their possible binding sites.
The continued interest in designing new macrocyclic ligands stems mainly from
their use in a diverse range of applications: for example, as models for protein-metal
binding sites in a range of metalloproteins, as synthetic ionophores, as models to study
magnetic exchange phenomena, as therapeutic reagents in chelation therapy for treatment
of metal intoxication, as cyclic antibiotics that owe their antibiotic actions to specific
metal complexation, in studying host-guest interactions and in catalysis [109, 110]. The
chemistry of macrocyclic complexes is also important due to their use as dyes and
pigments [111].
Metal ions that compose the vast number of complexes in general and the
macrocycle complexes in particular, play a vital role in a vast number of widely differing
biological processes. Some of these processes require a specific metal ion with specific
oxidation states that can fulfill the necessary catalytic and structural requirements, while
other processes may be much less specific with most probable reduced activity [112].
Macrocyclic compounds and their derivatives are interesting ligand system because they
are good hosts for metal anions, neutral molecules and organic cation guests [113].
Macrocyclic compounds are also important for their capacity for recognition of metals of
biochemical, medical and environmental importance [114, 115]. The metal ion and host–
guest chemistry of macrocyclic compounds is very useful in fundamental studies, e.g. in
phase transfer catalysis and biological studies [116].
There is continued interest in synthesizing macrocyclic complexes because of
their potential applications in fundamental and applied sciences [117, 118]. Synthetic
macrocyclic complexes mimic some naturally occurring macrocycles because of their
resemblance with many natural macrocycles like metalloproteins, porphyrins and
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cobalamine [119-124]. So biologically active macrocyclic complexes are used in the
identification of diseased and normal tissues [125]. Transition metal macrocyclic
complexes have received a great attention because of their biological activities, including
antiviral, anticarcinogenic [124], antifertile [126], antibacterial [127-129], antifungal
[130-133], antitumor, anticonvulsant [134] and catalytic [135] activities. The available
literature has also evidenced about their antioxidant [136] and anti HIV activities [137].
Transition metal complexes also used as MRI contrast agents [138-141], NMR shifts
reagents [142] , sensitizers in dye sensitized solar cells, diet supplementation[143] and
catalytic cleavage of RNA and DNA [144]. Metal complexes having the ability to bind
and cleave double stranded DNA under physiological conditions are of great importance
because of their applicability as drugs [145-148]. Platinum-based drugs are most widely
studied and these interact with DNA mainly through the formation of intra-strand cross-
linked adducts located in the major groove which in turn is responsible for their antitumor
properties [147]. However, the platinum-based drugs suffer from their severe toxicity. So
the interest has been focused to the other metal-based drugs which bind DNA [149-162].
The synthesis of azamacrocyclic compounds received considerable attention
during the last decade because of their relationship to biomimetic and catalytic systems
and the applications of this type of chelating agents to biology and medicine. They have
applications in modern chemical techniques such as magnetic resonance imaging,
imaging with radioisotopes and radiotherapy, i.e. techniques where metal complexes with
extreme kinetic and thermodynamic stability toward metal release are required [163,164].
There has been a particular interest in the preparation and characterization of coordination
compounds with macrocyclic ligands with pendant substituents for the reasons given
above [165-169]. The complexation properties of polyazamacrocycles are governed
mainly by the macrocyclic ring size. N-Functionalization of these macrocycles may
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enhance their metal-ion selectivity and the stability of metal complexes depending on the
coordination properties of the pendant arms [165]. Molecular recognition of DNA, RNA
and related biomolecules by complexes with azamacrocyclic ligands has attracted great
interest [170,171].
Aza type ligands appear very promising in many biological properties like
antibacterial, antifertile, and antifungal agents [172- 175]. Transition metal complexes
have played important role as catalysts in the oxidation and epoxidation processes [176].
Structural factors such as ligand rigidity, the type of donor atoms and their disposition
have been shown to play significant roles in determining the binding features of
macrocyclic ligands toward metal ions [177, 178].
Moreover, those which bear additional pendant coordinating groups have been
found to be particularly valuable, as their properties and selectivity for certain metal ions
over others may be quite different from those of the unsubstituted parent macrocycles
[179,180]. Transition metal complexes of polyazamacrocyclic ligands have significant
industrial application as thermodynamic and kinetic inertness [181]. Several articles have
been published that cover the various aspects of polyazamacrocyclic complexes [182].
1.10. Aims and objectives A search through the literature has clearly revealed that there is a continuing
interest in the field of immobilizing transition metal complexes on different supports.
Attempts of anchoring metal complexes on different supports are even now extensively
studied. Synthetic macrocycles and their metal complexes in general and
polyazamacrocycles in particular could play essential roles in diverse chemical and
biological applications such as antiviral, anticarcinogenic, antifertile, antibacterial,
antifungal, antitumor, anticonvulsant, antioxidant, and binding and cleavage of DNA
and catalytic activities.
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Therefore, it was thought worthwhile to synthesize and characterize some
azamacrocyclic metal complexes of the biologically important ligands utilizing the most
modern techniques. The author has carried out the synthesis, characterization and
applications, and details are as under.
Overview of literature survey of the coordination compounds in general and
azamacrocyclic complexes in particular.
Synthesized several azamacrocycle ligands and its metal complexes in pure state.
Purity of synthesized complexes was checked using HPLC.
Key features of coordination compounds were studied: - structure of coordination
compounds by magnetic susceptibility measurement and electronic spectral data
along with elemental analysis, 1H NMR, IR, melting point, molar conductivities
and the stability of the complexes by thermal analysis.
Color properties of transition metal complexes were studied in terms of Crystal
Field Theory.
Jahn-Teller distortion in terms of d-electron count were studied.
Synthesized complexes were evaluated for biological applications like antimicrobial,
antioxidant, xanthine oxidase enzyme inhibition, docking studies, anticancer and binding/
cleavage of DNA and industrial catalysis for conversion of benzyl alcohol to
benzaldehyde.
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