TERM PAPER

CHEMISTRY

CHE 101

Topic: Metallodrugs

DOA: 26-Aug-2010

DOR: 28-Sep-2010

DOS: 8-Nov-2010

Submitted to: Submitted by:

Ms. Geetika Arora Mr. Aditya Raj Verma

Deptt. Of Chemistry Roll. No. RE6001B60

Reg.No.11004066

Class. B Tech-MBA(ece)
 METALLODRUGS

Aditya Raj Verma

RE6001B60

|
 ACKNOWLEDGEMENT

I am heartily thankful to my teacher Geetika Arora whose encouragement, guidance and

support from the initial to the final level enabled me to develop an understanding of the
subject. My sincere thanks to my parents for their moral support and believe in me in
completion of my project.

I also owe my sincere thanks to Mr. James A. Cowan for their review on catalytic
metallodrugs which helped me to understand the future perspective of metallodrugs.

Lastly, I offer my regards and blessings to all of those who supported me in any respect
during the completion of the project.

Aditya Raj Verma

 TABLE OF CONTENTS

1. Abstract……………………………………………….1

2. Introduction…………………………………………..2

3. History of metallodrugs……………………………...2

4. Toxicity of metals…………………………………….3

5. Metals used…………………………………………...5
• IRON

• PLATINUM

• TITANIUM

6. Metal based drugs……………………………………7

7. Mechanism……………………………………………8

• Chromodulin

• cisplatin

• Aurothioglucose

8. Catalytic metallodrugs………………………………13

9. Design and function………………………………….14

10. Conclusion…………………………………………….16

11.References…………………………………………….16
ABSTRACT

In medicinal chemistry metal complexes as pharmaceuticals have received limited attention

compared with organic compounds. Much of the attention has been given to Pt(II) complexes
that inhibit tumor growth, but a widely applicable target for development of metal complexes
as pharmaceuticals has emerged from new perspectives of enzymes in disease processes. In
this review we look at work involving the mechanism, application and types of metallodrugs
complexes as pharmaceuticals, and what this work reveals about transport of metal
compounds across cell membranes and future roles for metallodrugs.

Further this review also highlights few metallodrugs with their complete mechanism for
complete understanding that what happens at cellular level.

It also includes an article on catalytic metallodrugs-future metallodrugs and its importance in

the medicinal chemistry.
INTRODUCTION
Metals have played an important role in medicine for years, ever since
humans have walked the planet. Many are essential in our diets in varying
quantities, although people have recently realized their significance. This
could probably be attributed to our increased awareness of personal and
families’ health and increased media involvement in our life. Many
metallic elements play a crucial role in living systems. A characteristic of
metals is that they easily lose electrons from the familiar elemental or
metallic state to form positively charged ions which tend to be soluble in
biological fluids. It is in this cationic form that metals play their role in
biology whereas metal ions are electron deficient, most biological
molecules such as proteins and DNA are electron rich. The attraction of
these opposing charges leads to a general tendency for metal ions to bind
to and interact with biological molecules. This same principle applies to
the affinity of metal ions for many small molecules and ions crucial to life,
such as oxygen. Since nature has made such extensive use of metal ions
in biological systems, the following questions arise:

Can metal ions be incorporated into drugs?

The question gave rise to term or the era of metallodrugs with well known
antitumor drugs widely used the cisplatin [Pt (NH3)2Cl2]. Inorganic or metal-
containing medicinal compounds may contain either (a) chemical elements essential to life
forms—iron salts used in the treatment of anaemia—or (b) nonessential/toxic elements that
carry out specific medicinal purposes—platinum-containing compounds as antitumor agents
or technetium and gadolinium complexes as medical diagnostic tools.

HISTORY OF METALLO DRUGS

Medicinal inorganic chemistry has been practiced, however, for almost 5000 years. As far
back as 3000BC the Egyptians used copper to sterilize water. Gold was used in a variety of
medicine in Arabia and China 3500years ago, more as a result of the precious nature of gold
than of its known medicinal activities. Various iron remedies were used in Egypt about
1500BC, around the same time that zinc was discovered to promote the healing of wounds. In
Renaissance era Europe, mercurous chloride was used as a diuretic and nutritional
essentiality of iron was discovered. It is in the last 100years, however, that the medicinal
activity of inorganic compounds has slowly been developed in a rational manner, starting in
the early 1900s with K [Au (CN)2] for tuberculosis, various antimony compounds for
leishmaniasis, and the antibacterial activity of various gold salts in a number of different
conditions. When one thinks of drugs, one often thinks of organic compounds such as the
antibacterial penicillins, the nutrient vitamin C and the psychoactive drugs, such as LSD,
THC, etc. The Biochemical literature of the last 30years chronicles the burgeoning
understanding that many of the biological activities of proteins and enzymes can be ascribed
to the metal centres, with the organic backbone acting as a scaffold to hold the metal ion in
place for the requisite transformation. Because of this rapid growth of biological inorganic
chemistry, it seems logical to explore in parallel the medicinal properties of the various metal
ions that are found naturally and even of those that are not found naturally and even of those
that are not known to have essential benefit. In the last 50 years, knowledge of the central
importance of inorganic elements in organisms has opened up the possibility for inorganic
chemists to contribute to health and well-being of man and all other organisms. It is ironic to
note that the first structure-activity relationship, which was developed by Paul Ehrlich in the
first decade of the 20th century, involved the development of the inorganic compound

arsphenamine (otherwise known as Salvarsan or Ehrlich 606) as a successful treatment for

syphilis. Ehrlich was the founder of chemotherapy, which he defined as the use of drugs to
injure an invading organism without injury to the host? He also discovered the preferential
accumulation of lead in the central nervous system, first formulated the chemotherapeutic
index as well as the “magic bullet” concept, and was awarded the Noble Prize in 1908 for his
discovery of immunochemistry.

You may be wondering that metallodrugs has very effective and powerful work in
treatment of many fatal disease but these drugs at the same time can be fatal too. So it
is important to discuss about the toxicity of different metals before we move on to the
various forms of metallodrugs.

TOXICITY OF METALS

Although many elements and compounds are required at some dosage for an organism’s
survival, all elements and compounds may be deleterious if taken in overly large doses. Some
elements and compounds are required in a certain range of concentration, while some appear
to be toxic at minimal dosage levels. Two examples of the latter are elemental lead and
mercury as well as their compounds. While these elements have always been present in our
atmosphere, they are especially dangerous because they form long-lasting compounds with
organic species and accumulate low in the food chain. Lead, mercury, and thallium appear to
be dangerous no matter how they appear in biological species. While chromium is an
essential element required for normal carbohydrate and lipid metabolism and its deficiency
can lead to adult onset diabetes, Cr(VI) uptake through anion channel transport into cells via
CrO2 causes several toxic effects. Following reduction inside cells, Cr(III) forms adducts
involving the phosphate backbone of DNA, the N7 atom of guanine, amino acids such as
cysteine, glutathione, and larger peptides and protein molecules. The table below may give
you some idea of the toxic metals and their effect on biological systems:-

METALS EFFECT COMMENT

Aluminium(Al3+) Implicated in May interact with
Alzheimer’s disease phosphates, may cross-link
proteins.

Cadmium(Cd2+) Renal toxicity Blocks sulfhydryl groups in

Mercury(Hg2+) Damage to central
nervous system,
neuropsychiatric
disorders
Lead (Pb2+) Injuries to peripheral
nervous system, disturbs
heme synthesis and
affects kidneys
Enzymes and competes with
zinc. Stimulates
metallothionein synthesis and
interferes with Cu(II) and
Zn(II) metabolism.
CH3Hg+ compounds are
lipid-soluble.
Pb2+ may replace Ca2+ with
loss of functional and
structural integrity.

Any metal ion or complex, or indeed any chemical compound, is subjected

to the potential limitations in the Bertrand diagram, which is usually used
in discussing the essentiality of elements. The area of optimum
physiological response will vary greatly according to the element, its
speciation and oxidation state and the biochemistry of the specific
compound in which it is found. Therefore, the areas of deficiency, toxicity
and optimum physiological response can be dramatically varied by
considering a combination of these variables, as well as design features of
the potential ligand which may be altered to tune the delivery of that
metal ion into the biological system.

Which of the metal are used in metallodrugs?

At present there are three important metals forms the base of

metallodrugs in medicinal chemistry. Let’s discuss them in detail as it
helps us to understand the elementary working of any metallodrugs:-

• IRON

Iron complexes were the earliest metal compounds to be studied in

medicinal chemistry. They were and are used to treat hypochromic
anaemia caused by iron deficiency. Clinical experience has
revealed Fe(II) to be better absorbed than Fe(III) when given orally
for this disease . The first mechanism identified for transport of
Fe(II) through cell membranes was endocytosis. In this
process transferrin, an Fe(II)-protein complex, is internalized by cell membranes as the protein binds
to specific receptors on the outside of cells. Transport through the membrane results from Brownian
motion of the receptors, with or without transferrin attached, as they continually move back and forth
between the inner and outer membrane surfaces. Endocytosis of Fe(II) is a highly organized and
regulated process the time frame of which is no more than a few minutes, possibly a few seconds.
Recently another mechanism for Fe(II) transport was identified , which does not involve endocytosis.

ENDOCYTOSIS

This mechanism appears to use the trans-membrane protein DCT1 identified by Gunshin . Ideal
conditions for Fe(II) transport by DCT1 exist in the upper section of the small intestine (duodenum)
closest to the stomach where pH increases from 2 to 7 as iron moves down the duodenum. (Little or
no transferrin or apotransferrin is present in the duodenum to facilitate endocytosis of iron.) Under the
pH conditions of the duodenum Fe(II) is free from hydrolysis and formation of insoluble hydroxides
and oxides, while Fe(III) is not. Thus, oral administration of Fe(II) complexes is more efficacious than
those of Fe(III) in alleviating the iron deficiency of hypochromic anaemia.

• 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
that some Group VIIIb metal complexes inhibit cell di6ision, and
quickly lead to study of Pt(II) complexes as agents capable of
stopping tumor growth . The first Pt(II) complex to be licensed for
this purpose was cisplatin, cis- [Pt(NH3)3Cl2. The discussion here
focuses on organizing and understanding the medicinal chemistry of Pt(II) chloroammine( amine)
complexes. In general such complexes are square-planar, and though inert with regard to the kinetics
of ligand exchange they do undergo reaction slowly. The action of cisplatin as an anticancer drug is
believed to result from binding of Pt(II) to cell DNA . Correlation between Pt–DNA binding and cell
death by apoptosis has been reported . A variety of Pt(II)–DNA adducts have been identified in non-
cellular systems . The adducts include Pt(II) bridged intrastrand and inter-strand DNA complexes,
with a preference for Pt(II) binding to N-7 in the guanine rings along the DNA chain . It is not known
which Pt(II)–DNA complex is critical to the mode of action, but adenine–Pt(II)–guanine adducts and
guanine–Pt(II)–guanine adducts of DNA have been proposed .

• TITANIUM
The earliest reference to medicinal chemistry of Ti(IV) is by
the German physician Julius Pick . He found
Tiandisulfataufschwemmlosung
(hydrolysed 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, a und b Naphthol, which were tested in animals before
settling on titanium sulphate and salicylates as being non-toxic.
For treatment of tuberculosis infection of the skin, Pick used a 0.25–0.5% Ti(SO 4)2 suspension in
water (gel), or 1–3% Ti(IV) salicylate in Vaseline applied to the infected area. The time required for
complete resolution of skin infections depended on the age of the infection, with older infections
being stubborn. For infection of the eye, a 0.05–0.1 g of Ti(SO4)2 in 100 g of sterile, distilled cold
water was filtered and two or three drops of the filtered solution applied 1 or 2 times daily.
Improvement of the involved areas was seen within a week. For tuberculosis infection of the
respiratory track (including lungs), a suspension of 0.25% Ti(SO4)2 and 0.25% Ti(IV) salicylate in
water was sprayed in the throat and 4 teaspoons (1 to 2 mg Ti per teaspoon) of Ti(IV) salicylate given
orally each day. After 6 weeks of treatment all symptoms were gone. Confirmation of tuberculosis
before Ti(IV) treatment was made by identification of Tuberkelbacillen im Sputum.

That was a brief description about some basic metals which laid
the foundation of metallodrugs. Few more compound included are
Gold, Silver, Magnesium, Cobalt, Zinc and few more are also
found used in many metallodrugs.

METAL BASED DRUGS

Previously I discussed about three metals Iron, Platinum and Titanium

which were the building blocks of metallodrugs. Now a little description
about the primary drugs used in pharmaceutical industries and their role
in preventing many fatal diseases.

Metal ions play a key role in the actions of synthetic and natural
metalloantibiotics, and are involved in specific interactions of these
antibodies with proteins, membranes, nucleic acids and other
biomolecules. For example:-

 The binding of Fe/Co-Bleomycin, Fe/Cu-Streptonigrin, Mg quinolone,

Mg quinobenzoxazine, Mg-Aureolic and cisplatin with DNA impairs
DNA function or results in DNA cleavage.

 The involvement of Mg/Fe in the binding of tetracyclines.

 The binding of metallobacitracin to undecaisoprenyl pyrophosphate

prohibits the recycling of the pyrophosphate to phosphate which
inturn inhibits cell wall synthesis.

 The binding of metal ions to siderophores or ionophores allows their

transport through cell membrane which can cause disruption of the
potential across the membrane.
Numerous examples of these “metallodrugs” and
“metallopharmaceuticals”:-

 aspirin and its metabolite salicyl glycine

 ibuprofen, the indole derivative indomethacin
 bioflavonoid rutin
 diclofenac
 suprofen
Some drugs get stabilized because of metallic part present in it as mentioned below:-

• The potent histamine H-2-receptor antagonist cimetidine can form complexes with
Cu2+ and Fe2+
• the histidine H2 blocker antiulcer drug famotidine can also form stable complex with
Cu2+
• thiabendazole, which is used for the treatment of several parasitic diseases, forms a
complex with Co2+
• the Ru2+ complex of the antimalarial agent chloroquine exhibits an activity two to five
times higher than the parent drug
• the antiviral trifluoperazine forms complexes with VO2+,Ni2+,Cu2+,Pd2+ and Sn2+ which
exhibit higher inhibition activities than the metal-free drug
• the clinically useful -lactamase inhibitor sulbactam can form complexes with
Ni2+,Cu2+ and Fe3+

More applications of metallodrugs

There are also a number of metallodrugs and metallopharmaceuticals which have been
utilized for the treatment of diseases and disorders or as diagnostic agents, such as

• gold antiarthritic drug

• bismuth antiulcer drugs
• gadolinium MRI contrast agents
• technetium radiopharmaceuticals
• vanadium as insulin mimics
• Lithium psychiatric drugs.

The metal ion Li+ can be considered the smallest effective metallodrugs
whose carbonate and citrate salts exhibit significant therapeutic benefit in
the treatment of manic depression. The metal ion Sb3+ may be regarding
as the simplest “metalloantibiotics” whose salts (including N-
methylglucamine antimonite and Na-stibogluconate) have been utilized
for the treatment of leishmaniasis against the protozoan parasite
Leishmania. The antiprotozoal mechanism of Sb3+ is thought to be
attributed to its binding to trypanothione that is essential for the growth of
the parasite.

After this long description of metallodrugs the next question in my mind is,

How these drugs work?

The nature of the target to be attacked by any drug obviously depends on
the specific application; many cytotoxic metal complexes target DNA
because of its importance in replication and cell viability. Coordination
compounds offer many binding modes to polynucleotides, including outer
sphere non covalent binding, metal coordination to nucleobase and
phosphate backbone sites, as well as strand cleavage included by
oxidation using redox-active metal centres. The later transition metals
such as platinum and ruthenium favour binding to electron-rich nitrogens
on the bases, especially guanineN7.Titanium and early metals may
display a mixture of nucleobase and phosphate backbone binding.

This advantage of transition metals make us able to design such complex

metallodrugs as some mentioned below:-

• Chromodulin

The holochromodulin binds to the insulin-stimulated insulin receptor, helping to maintain

its active conformation and increasing insulin signalling. It is known that part of this
process involves the 80-kDa blood serum protein transferrin that tightly binds and
transports two ferric iron ions. Because the iron binding uses only 30% of transferrin’s
metal binding capacity, it has long been thought to bind and transfer other metal ions
(including perhaps chromium) in vivo.

Figure below describes the mechanism of chromodulin:-

Platinum-Containing Anticancer Agents
From the above mechanism it is clear that the main target of any metallodrug is protein based
linkage present in the human body as present as DNA and RNA in cell protoplasm. The next
metallodrug is widely used in treating tumours as anti cancer drug.

Cisplatin

Its base metal atom platinum works on DNA and targeting the cells causing tumour.
At the beginning of its history as an anticancer agent, it was found that cis-[Pt(NH 3)2Cl2]
inhibits DNA replication. Before any reaction can take place between cisDDP and DNA, the
platinum drug must enter the cell. This is believed to take place through passive or active
diffusion, although the process is not well understood. It is known that in the bloodstream,
cisDDP retains its chloride ions because Cl- concentrations are high (0.1 M). Inside the cell,
chloride concentration is much lower (0.004 M) and equilibria are established for the
hydrolysis reactions shown in below figure.

Because the chloride ion is a better leaving group than the ammonia ligand, which forms a
more thermodynamically stable covalent bond with metal ions, the ammine ligands remain
while chloride ions are displaced by water. This aqueous chemistry for platinum(II)
compounds, more complex than shown in Figure because various OH- as well as H2O ligand
combinations are possible at physiological pH, has been exhaustively studied and reviewed
Water ligands in turn are replaced by nucleobase ligands from DNA strands; once formed,
these nucleobase nitrogen attachments are thermodynamically stable. The preferred point of
attachment along DNA strands has been found to be at the guanine N7 position. The most
likely sequence of events is the hydrolysis of one chloride ligand followed by reaction with a
dsDNA guanine ligand, hydrolysis of the second chloride ion, and attachment of a second
dsDNA guanine.

We have seen how cisplatin binds DNA, and now we want to understand how the binding of
cisplatin to DNA leads to programmed cell death. Researchers have found that this binding
affects both replication and transcription of DNA, as well as mechanisms of DNA repair. The
effects of both cisplatin and trans-DDP on DNA replication were studied both in vitro (using
cell extracts outside the host organism) and in vivo (inside the host organism). In vitro studies
on both prokaryotic (bacterial) and eukaryotic (mammalian) cells revealed that DNA adducts
of both cisplatin and trans-DDP blocked the action of DNA polymerase, an enzyme
necessary for replication. In particular, 1,2-intrastrand adducts of cisplatin with DNA all
stopped polymerases from doing their job. Likewise, in vivo studies showed that cisplatin and
trans-DDP inhibited replication equally well. Since other studies have shown that cisplatin is
an effective antitumor agent but trans-DDP is not, these results suggest that DNA replication
is not the only factor important for the clinical activity of cisplatin in destroying cancer
cells.1 The effects of cisplatin and trans-DDP on DNA transcription are harder to interpret
than the effects on replication. However, cisplatin does not appear to inhibit transcription,
possibly leading to programmed cell death.

The below flowchart may clear the mechanism of cisplatin

Aurothioglucose-gold based metallodrug

Also known as gold thioglucose is a

chemical compound with the formula
AuSC6H11O5. This derivative of the sugar
glucose is used to treat rheumatoid
arthritis.

The mechanism by which gold drugs

operate to treat arthritis is a matter of
scientific debate. Of the various mechanisms that have been suggested for the transportation
of the drugs to their sites of action in the synovium, it is thought that in the blood stream the
gold attaches to albumin. The thiol groups on the gold drug being exchanged for the cysteine
cysteine-34 of this protein. After arrival at the synovium, the Au(I) again undergoes a second
thiol exchange reaction at cell membrane transport proteins and enters the cell via the shuttle
thiol mechanism. Once absorbed into the cell, gold is proposed to be linked to anti-
mitochondrial activity and induced cell apoptosis. The myriad of side effects associated with
this class of prodrugs is ascribed to the non-specific absorption and pharmacological action,
thus many cells not linked with the rheumatoid arthritis immune response are affected. Some
assert that gold drugs merely inhibit the function of the various components of the immune
response associated with rheumatoid arthritis, rather than acting in a disease curing fashion. It
is thought that gold affects the entire immune response (phagocytes, leukocytes, T-Cells...)
and reduce its potency and limit its oxidizing nature, ending the cycle of joint inflammation
and erosion.

CATALYTIC METALLODRUGS-Future of metal based medicine

The development of a new paradigm for therapeutic action–catalytic

metallodrugs (Figure). Such molecules include both a metal binding
domain (to catalyze oxido-reductase chemistry on proteins and nucleic
acids) and a target recognition domain (Figure), and have the potential to
act on therapeutic targets with regulatory or functional roles that are
either essential for pathogen or viral survival, or inactivation of disease-
related enzymes.
DESIGN AND FUNCTION OF CATALYTIC METALLODRUGS

Since proteins and many RNAs possess tertiary structure that is required for activity and/or
function, these are the two families of macromolecules that have formed the focus of the
studies. While catalytic metallodrugs may retain classical inhibitory properties, they also
show the potential for catalytic degradation of the drug target (Figure). Irreversible
destruction of target also affords the potential for substoichiometric administration of drug,
with the promise of a significant lowering of dosage and a commensurate decrease or
elimination of side effects or toxicity. This key point differentiates the activity of catalytic
metallodrugs relative to the high affinity binding that is essential for the classical inhibitory
mechanism of drugs currently on the market.

A combination of reversible binding and irreversible chemistry yields a novel double-filter

mechanism for target recognition that is illustrated in Figure. If two proteins (or RNA
motifs), A and B, are recognized by the targeting domain of the drug, but only protein A has
a suitable orientation for chemical inactivation by the catalytic metal domain, then only
protein A would be irreversibly inactivated by the metallodrug (Figure). The use of a sub
stoichiometric concentration of drug ensures that the majority of protein B is not influenced
by the metallodrug. Of considerable practical significance is our observation that such metal-
binding peptides can be delivered in a metal-free state with subsequent recruitment of
intracellular metal cofactors avoiding toxicity and regulatory problems that might stem from
delivery of exogenous metal cofactors.

A hope for HIV treatment:-

Traditional drug development has focused primarily on protein targets, reflecting the diverse
structural and catalytic roles of cellular proteins that provide targets in metabolic and
infectious disease. The complexity of protein structure also affords an opportunity for
selective recognition by organic molecules, using spatial and bonding constraints to map
drugs to protein targets. Likewise, many retroviruses and pathogens contain important RNA
sequences that can both adopt comple x tertiary structural motifs and are amenable to
selective binding by drug molecules. Most important, there is no cellular repair mechanism
for RNA, and so compounds that are capable of specific or selective binding to RNA should
be considered in developing effective chemotherapeutic treatments Productive HIV infection
is dependent on the interaction of a regulatory protein, Rev, with a specific RNA structure
known as the Rev-responsive element or RRE. The RRE is a 234-nucleotide RNA sequence
embedded within the viral env-coding region. The high affinity Rev binding site, or core
element, within the RRE consists of a stem-bulge-stem structure. Cedergren and coworkers
have demonstrated in a study of the occurrence of specific viral (and other) RNA motifs in
native host cells that critical viral sequences such as the core of the HIV RRE are under-

represented in natural genomic sequences. Such sequences are suggested to have a

detrimental influence on cell growth or viability, and so there is a minimal possibility of
interference from natural sequences of similar structure. Since the RRE-Rev interaction is
essential for viral replication, it is an attractive target for antiviral therapy against which there
is no current commercial drug. Our concept of a catalytic metallodrug, capable of
irreversible, multiturnover degradation of a therapeutic target has been tested against HIV
RRE RNA, both in vitro and in cellular assays. Figure 4 illustrates a family of N-terminal
metal binding ATCUN motifs that are extended to include the RRE RNA recognition peptide
through a variable-length glycine linker sequence (Gx, x = 0, 1, 2, 4, 6). The binding affinity
of both the Rev1 and Cu-Rev1 peptides to the fluorophor-labeled RRE RNA determined to be
~30 and 35 nM, respectively. These numbers are consistent with published data for binding
of the native Rev peptide lacking the ATCUN motif.

ZINC-METALLOPROTEASES AS DRUG TARGETS IN CARDIOVASCULAR

DISEASE

The family of zinc metallopeptidases involved in cardiovascular regulation includes

angiotensin converting enzyme (ACE),
endothelin converting enzyme (ECE-
1), and neprilysin (NEP). ACE and
ECE-1 are involved in the generation
of the strong vasoconstrictors
angiotensin II (Ang II) and endothelin I
(ET-I) that are derived from the inactive precursors angiotensin I (Ang I) and endothelin,
respectively, while ET-I is degraded by NEP. There is substantial interest in evolving
compounds with synergistic therapeutic profiles in comparison to individual selective
inhibitors. Since NEP achieves the degradation of ET-I, inhibition of the former results in
increased plasma levels of ET-I, thereby limiting the application of the dual NEP/ACE
inhibition approach. This problem could be overcome by inhibiting ECE-1, and a common
zinc metalloprotease inhibitor for ACE, NEP, and ECE-1 would be an ideal drug candidate.
Typically, cardiovascular drugs are based on inhibition of ACE, ECE, or NEP, and are
blockers of receptors that depend on the product formed by these proteases (such as AT2
receptor blockers). In addition to these, a small number of drugs that act by a dual mechanism
(such as the calcium channel adrenergic blockers 1, calcium channel α1 adrenergic blockers,
5HT 2A antagonists, endothelin and angiotensin receptor blockers, ECE and ACE inhibitors,
and NEP and ECE inhibitors) increasingly
present an alternative therapeutic approach.

CONCLUSION

A significant rising interest in the design of metal compounds as drugs and diagnostic agent
is currently observed in the area of scientific inquiry appropriately termed medicinal
inorganic chemistry. Investigations in this area focus mostly on the speciation of metal
species in biological media based on possible interactions of these metal ions with diverse
biomolecules, in an effort to contribute to future development of new therapeutics or
diagnostic agents.

The report provided may also give us hope for future medicines which may interact fully with
biological system with no toxicity or side effects as these medicines may become the part of
the for curing many fatal diseases. Metallodrugs are the field which need more
understanding, research and exploration as I find that these drugs are the future drugs with
more precise and significant role to play in medical science.

Metallodrugs also lay a path for many chemist to explore the interaction of organic part with
metal ions and also imparting cells with more power and resistance for complete eradication
of diseases from the body.

References:-

 www.wikepedia.com
 www.osu.edu/units/reseach
 www.ajrconline.org
 Organometallic compounds
 Coordination compounds in medicinal Chemistry by Chad W. Schwietert
 A review on Catalytic metallodrugs by James A. Cowan
 Metals in medicine by Rosette M. Roat-Malone