Copper complexes as anticancer agent

2. Table of contents
 Introduction
 Need of metal ion in biological system
 Analytical technique characterisation
 Copper chemistry
 Copper based complexes as anti cancer agent
 Copper (II) complexes
 Copper (II) complexes of semicarbazone
 Copper (II) complexes of macro cyclic ligand
 Toxicity issues in the use of metal complexes as anticancer
drugs
 Conclusion
 References

3. Introduction
 Cancer is a term used for diseases in which abnormal cells
divide without control and are able to attack other tissues.
 Cancer cells can spread to other parts of the body through the
blood and lymph systems.
 Cancer it is a class of diseases characterized by uncontrolled
proliferation of cells.
 Dedifferentiation, Loss of function,attack to local tissues,
Spread or metastasis to other parts of the body.
 Cancer is not a single diseases.It is a group of more than 200
different diseases.
 Cancer may spread to other parts of the body.
 Around 15 lack new cases are diagnosed every year in India.

4.  The medical term for tumor (or) cancer is Neoplasm, which
means a relatively autonomous growth or un coordinated cell
proliferation of body tissue.
 The term Neoplasm means New growth &the process of cell
proliferation is called Neoplasia.
 The branch of medicine which deals with the excessive study
of neoplasm (tumour and its development diagnosis and
treatment is called “Oncology”.

5. Need of Metal ion in biological system
Metal ions play tremendous role in biological system
predominantly in the cationic form

6. Need of metal ion in biological system
Metal ions can have structural role, functional role & both
Metal Function
Na+ , K+ Charge carrier, osmotic balance
Mg2+, Zn2+ Structural hydrolase, isomerase
Ca2+ Structural, charge carrier
V2+, Mo3+ Nitrogen fixation, oxidase
Mn2+ Photosynthesis, structural, oxidase
Ni2+ Hydrogenase, Hydrolase
Fe2+, Cu2+ Dioxygen transport & storage, electron transfer, oxidase
Knowing the essential role of metal ion in biological system the
use of metal complexes as therapeutic agent is the natural step
in medicinal chemistry

7. Analytical technique - characterization
Ligands Metal complex
FT-IR spectroscopy Elemental analysis
Electronic absorption
spectroscopy
FT-IR spectroscopy
Fluorescence spectroscopy ESI-Mass spectrometry
Nuclear magnetic resonance
spectroscopy
Electron paramagnetic
resonance spectroscopy
ESI-Mass spectrometry Electronic absorption
spectroscopy
Fluorescence spectroscopy
Single crystal X-ray diffraction

8. Copper chemistry
 Humans primary used copper regarding 10000 years ago.
 Copper is the 29th chemical element of the Periodic Table and
present in the first row of Group 11 metals. And its electronic
configuration is 3d104s1. Therefore the Cu(I) ion has a
completed 3d10 shell and the Cu(II) ion, loosing two electrons,
has a partly filled d-block 3d9 configuration. So Cu behaving as
a general transition metal.
 Cupric and cuprous copper ions can take part in oxidation and
reduction reactions.
Cu(II) + O2
-• Cu(I) + O2
Cu(I) + H2O2 Cu(II) + OH• + OH-
O2
-• + H2O2 O2 + OH• + OH-

9. Cu-proteins and enzymes
 Cytochrome oxidase
 Tyrosinase, phenol oxidase
 Ceruloplasmin
 Blue proteins
 Superoxide dismutase
 Hemocyanin
O2→H2O
Ox. of phenols
Fe(II) → Fe(III)
Electron transfer
Elimination of O2
–
O2 transport
Biologically accessible redox potential
Cu(s)→ Cu2+ 2e− (-0.34 V)

10. Copper based complexes as anti cancer agent
 Anticancer copper complexes can be classified into two major
groups; copper chelators and copper ionophores.
 Copper chelators suitable copper ions from cells inside the
body and thus aim to limit cancer development by inquisitive
with increase and malignant processes.
 On the other hand, copper ionophores carrying copper into
cells growing intracellular levels and applying cytotoxic
consequences through a numerous of passageways.
 Many copper ionophores liberate coordinated copper below
the reductive intracellular environment, allocating copper to
become bioavailable and such compounds are generally more
capable at killing cancer cells.

11.  Copper is an crucial trace nutrient to all important plants and
animals.
 In mammals, it is found mainly in the bloodstream, as a
cofactor in different enzymes, and in copper-based pigments.
further than a total of 80-120 mg in a healthy human adult of
70 kg there are 8 mg in liver, 15 mg in heart, kidneys, brain
and blood.
 On the other hand, in adequately high amounts, copper can
be toxic and even deadly to organisms.
 In the form of bivalent ion, copper is extremely poisonous to
lower organisms.
 For instance, bacteria and other decompose micro-organisms
die in water in a copper container, and copper compounds in
universal prevent growth of algae.

12. Copper(II) complexes
 The common oxidation states of copper are +1 and +2,
although copper(I) compounds are generally unstable towards
oxidation to the copper(II) form and are less studied as
anticancer compounds.
 The ability of copper to undergo facile cycling between +1
and +2 oxidation states enables it to serve as a catalytic center
in many redox enzymes.
 Generally, copper(II) complexes, being redox active, stimulate
the production of reactive oxygen species that cause DNA
damage in cancer cells.

13. Copper(II) complexes of semicarbazones
 Copper(II) salicylaldehyde semicarbazone complexes that show
anti-tumor activity against the human breast cancer cell line MCF7
(1a &1b, Figure 1)
 The activity of these complexes was attributed to their ability to
generate considerable intracellular oxidative stress via the
Cu2+/Cu+ redox couple.
Figure 1

14.  Another series of copper(II) salicylaldehyde semicarbazone
complexes (2–8, Figure 2) was synthesized and tested for
cytotoxicity towards MCF-7 and A-549 cells.
2: R1 = R2 = Me
3: R1 = R2 = Et
4: R1 = R2 = i-Pr
5: R1 = R2 = Ph
6: R1 = R2 = Benzyl
7: NR1R2 = Piperidyl
8: R1 = Ph, R2 = H
Figure 2

15. Copper(II) complexes of macrocyclic ligands
 Macrocyclic ligands offer the advantage of forming metal
complexes that are relatively stable under physiological
conditions.
 They can also be readily functionalized with groups that
confer water solubility and/or intraction with biomolecules
such as DNA.
 Copper(II) complex of 2,2,2´
,2´
-S,S- [bis(bis-N,N-2-
thiobenzimidazolyloxalato-1,2- ethane)] (Figure 3) binds to
DNA through partial intercalation, and that it possesses
excellent DNA cleavage activity .

16. Figure 3

17. Copper(II) complexes of biomolecules & their
derivatives
 The biocompatibility of biomolecules, most of which contain
donor atoms, makes them attractive candidates as ligands for
copper-based pharmaceuticals.
 Furthermore, since biomolecules are the natural substrates of
enzymes, their structurally similar metal complexes can
potentially act as competitive inhibitors and, hence, disrupt
key metabolic pathways in cancer cells.
 Copper complexes of l-glutamine Schiff bases (Figure 5) have
also been reported to have significant proteasome-inhibitory
activity in human breast cancer and leukemia cells.

19. Toxicity issues in the use of metal complexes as
anticancer drugs
 metal complexes are promising as anticancer drugs with fewer
side effects than cisplatin, there are toxicity issues to deal
with.
 Copper can become toxic for cells when it participates in the
formation of reactive oxygen species, which may increase the
risk of carcinogenic mutations.
 Mutations in ATP7B, a protein that mediates the clearance of
excess copper from the body, result in Wilson’s disease, in
which excessive copper accumulates in the body, especially
the liver.
 Accumulation of copper increases the risk of liver cancer and
can lead to the development of neurological impairment and
movement disorder.

20. Toxicity issues in the use of metal complexes as
anticancer drugs
 Copper also facilitates angiogenesis, one of crucial stages in
tumor growth, invasion and metastasis.
 It activates the angiogenic molecules, VEGF and FGF, and
increases their affinity for cell-surface receptors.
 Copper complexes of ceruloplasmin and heparin are also
angiogenic .

21. Conclusion
 Important attention in developing copper complexes for
cancer treatment has occur from understanding of the
significance of copper in cancer growth, malignant
angiogenesis, and metastasis.
 Copper, as an crucial cofactor in a number of enzymes and
physiological processes, possibly less toxic than non essential
metals, such as platinum.
 According to the well recognized coordination chemistry of
copper, normally enriched by the flexible Cu(I/II) redox
behaviour, there still exist an massive prospect in the design
of more potent and less toxic copper based antiproliferative
drugs.

22. Reference
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