understanding - 4

introduction - 4
literature - 4
conclusion - 2.4
format - 1.6

total = 16

CHM579
ADVANCED INORGANIC CHEMISTRY
TITLE:
“Application of Coordination Compounds in Daily Life”
Cu(II) thiosemicarbazone

PREPARED BY:

NUR SHAHIRAH BINTI AZHARUDIN (2020489762)

GROUP :
RAS2224A

PREPARED FOR:
DR. MOHAMMAD SAIFULDDIN BIN MOHD AZAMI

DATE OF SUBMISSION: 4 JULY 2022

ACKNOWLEDGEMENT ⅱ

INTRODUCTION 1

a. Background of The Issue 1

b. Objective or Purpose of The Report 1

c. Reports on problems 2

d. Scope of the Report and Sources 2

e. Personal Opinion On The Particular Issue 3

REVIEW OF LITERATURE REVIEW 4

a. Complex compound 4

b. Main biological activity 9

c. Advantage and disadvantage of the complex compound of case study 14

d. Example of similar complex compound can be used for the chosen case study. 19

CONCLUSION 21

REFERENCES 22

ⅰ
ACKNOWLEDGEMENT

First and foremost, we would like to thank our lecturer for this assignment Dr.

Mohammad Saifulddin Bin Mohd Azami for giving such helpful information to complete this

assignment. He expressed full support and provided us with the different teaching aids that were

required to complete this assignment. We are really grateful because we managed to complete

this assignment within the time given by our lecturer.

Last but not least, this report also will not be complete without the cooperation of our

group members. We also like to give appreciation to both our parents and family members who

have motivated us to work harder and give moral support to complete this assignment.

ⅱ
INTRODUCTION

a. Background of The Issue

Thiosemicarbazones represent a class of N,S-donor ligands important in

coordination chemistry. These ligands have great versatility, manifested by the existence

of two forms (thione-thiol), and the ability to bind metal ions acting as monodentate or

bidentate ligands. The cytotoxicity of these ligands is enhanced by coordination to metal

ions such as copper, zinc, platinum and palladium. The coordination compounds find

wide application in different aspects of daily life. In this issue, we will discuss the

application of Cu(II)thiosemicarbazone complex compounds in daily life specifically.

b. Objective or Purpose of The Report

First of all, the objective of this report is to learn about the coordination

compound that we have chosen, which is the Copper (ii) complex of thiosemicarbazone.

This report is written to study the importance of the complex compound of

thiosemicarbazones and preparation of the thiosemicarbazones. Besides, the report is also

written to study the characteristics of the ligand and its metal ion. The biological activity

of the Copper (ii) complex of thiosemicarbazone and its mechanism also need to be

highlighted in this report. Lastly, the objective is to list the advantage and disadvantage

of the complex compound and to give an example of the similar complex compound.

1
c. Reports on problems

Thiosemicarbazones that have been mostly characterized are sulphur and nitrogen

containing compounds. Thiosemicarbazone ligands and their metal complexes are of

great interest because of their biological activity. Due to this, many compounds derived

from thiosemicarbazone have been the subject of most biological studies. Some of the

thiosemicarbazone ligands have been found to be antibacterial, antifungal, antitumor,

antarthric, antiamebic, antiviral, specific anti-HIV.

The synthesis and characterization of thiosemicarbazone ligands containing

ferrocene or pyridine fragments has been published in the limited literature information

journal. Furthermore, nothing has been reported on the characterization of their copper

complexes. In several studies, the ligand and their copper complexes have been tested for

their biological activities against bacterial, fungal, tumor and viral infections. However

very little has been done on the test against malaria parasites. The test that was done by

Rodriquiz-Arguelles et al. (2005), against bacteria shows that the ligands do not have

biological activity, while their copper complexes have higher biological activity

compared to other metal complexes.

d. Scope of the Report and Sources

In this report, we analyzed the application of coordination compounds in daily life

from the complex compound and the selected ligand. Cu (II) thiosemicarbazone

complexes are antibacterial and antitumor agents. Cu (II) complexes exhibited excellent

anticancer and antimicrobial activity and greatly exceed the corresponding metal-free

ligands.

2
 The task for this report involved reviewing the importance of the compound,

analyzing the chemistry description on the preparation and the characteristics of the

compound, studying the mechanism of biological activity of the complex compound, and

assessing the advantage and disadvantage of the complex compound.

The scope of content included both modern and archival information. The report

focused on theoretical methodology. All the credibility of these information sources come

from various journals found from the internet. The sources were cited in the report and

referenced by the end of the report.

e. Personal Opinion On The Particular Issue

Thiosemicarbazone (TSCs) belongs to the inorganic metal chelators class and has

numerous forms that can be synthesized for anticancer properties. Thiosemicarbazone

can form complexes with various transition metals such as Copper and Nickel.

Thiosemicarbazone are well known for their broad spectrum of biological activity. The

coordination of TSCs to metal ions results in metal complexes with anticancer properties.

In this report, we have chosen Copper (ii) complexes as our complex compound. As we

go through the journals, we found that Cu(ii) complexes of thiosemicarbazone have an

antiproliferative activity which is similar to antitumor activity in which it inhibits cell

growth which is good to kill the tumor cell. By doing this report, we can explore more

about this specific coordination compound that really gives benefits to our life which is

the Copper (ii) complex of thiosemicarbazone.

3
REVIEW OF LITERATURE REVIEW

a. Complex compound

Importance of the compound

The metal that we choose in this experiment is Cu(ii). since, addition of metal and

ligand form coordination compounds. So, the complex compound for this assignment is

Cu(ii) thiosemicarbazones. Every compound has their importance, the same goes to the

compound Cu(ii) thiosemicarbazones. Thiosemicarbazones represent a class of N,S-donor

ligands important in coordination chemistry. These ligands have great versatility,

manifested by the existence of two forms (thione-thiol), and the ability to bind metal ions

which is Cu2+ in the neutral or anionic form, acting as monodentate or bidentate ligands.

Cu(ii) thiosemicarbazone complexes are of interest due their bioinorganic applications.

Thiosemicarbazones are well-known for their broad spectrum of biological

activity. p-Acetylaminobenzaldehyde thiosemicarbazone was used to treat tuberculosis

after the Second World War while 2-formylpyridine thiosemicarbazone was the first

discovered representative of this class of compounds with potent anticancer activity. To

date, the 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) remains one

of the most extensively studied TSC for cancer chemotherapy. Although Triapine entered

a number of clinical trials, it was later abandoned due to severe side-effects and limited

response to specific cancer types. So now we focus on the importance of copper(II)

thiosemicarbazones to be antifungal, antibacterial, antiviral, anti-inflammatory and

chemotherapeutic agents, potentially useful for inhibiting the activities of cancer cells.

4
Copper(II) complexes possess a wide range of biological activity and are among the most

potent antiviral, antitumor and anti-inflammatory agents. For example, a copper(II)

complex of 2-formyl-pyridine thiosemicarbazone has been shown to inhibit the

RNA-dependent DNA polymerases and the transforming ability of Rous sarcoma virus

(RSV). In addition, copper(II) complexes of 2-acetyl-pyridine thiosemicarbazones are

active antimalarial agents. They possess strong antineoplastic activity against a number of

transplantable tumors, spontaneous murine tumors and human tumors. The mechanism of

their antitumor action is thought to involve either inhibition of the enzyme ribonucleotide

reductase, an obligatory enzyme in DNA synthesis, or creation of lesions in DNA strands.

Preparation and the characteristic

Thiosemicarbazones are a group of sulfur derivatives of semicarbazones that are

obtained as a result of the condensation of appropriate aldehydes or ketones and

thiosemicarbazides in an acidic environment. Figure below shows the preparation of

thiosemicarbazone. The addition of lapachol and thiosemicarbazide will result in

thiosemicarbazone.

5
 As we know, the copper(II) complexes of thiosemicarbazone were prepared

according to the procedure below. A solution of the copper(II) chloride hexahydrate in

water was added dropwise while stirring the solution of the ligand thiosemicarbazone in

acetone. The precipitate was separated by filtration using micro-filter paper, washed

several times with ethanol, followed by diethyl ether and dried on a vacuum pump. The

synthesis of thiosemicarbazone complexes of the copper(II) metal is prepared.

There are several methods, conventional and modern, available to explain the

structure of ligands and their coordination compounds. The complexes are characterized

by elemental analysis, molar conductance, magnetic susceptibility measurement and

spectral. Thiosemicarbazones, with the general formula R1R2C=N-NH-C=S-NR3R4 are

one of the most important nitrogen sulfur donor ligands. Owing to the presence of the

–NH-C=S functional group, thiosemicarbazones exhibit thionethiol tautomerism and can

bind to the metal ion either in the anionic thiolate form or in the neutral thione form. The

C, H and N in the thiosemicarbazone can be analyzed on an elemental analyzer. The

nitrogen content of the complexes was determined using kjeldahl method. Elemental

analysis (EA) served as a principal tool to distinguish complexes from their starting

material.

Next, there are several types of spectral which are infrared spectroscopy,

electronic spectroscopy and Nuclear Magnetic Resonance ( 1HNMR and 13CNMR)

spectroscopy. Infrared spectra for copper(II) complexes shows that the functional group

stretching frequencies were significantly shifted to higher frequency relative to their

6
values in the corresponding ligand. This indicates that the functional group is

strengthened by complex formation. The vibrational states of a molecule can be probed in

a variety of ways. The most direct way is infra-red spectroscopy because vibrational

transitions typically require an amount of energy that corresponds to the infrared region

of the spectrum. Radiation in this region can be utilized in structural determination in

coordination chemistry by making use of the fact that interatomic bonds in ligands absorb

it. Electronic spectroscopy is the measurement of the wavelength and intensity of

absorption of near ultraviolet and visible light by a sample. UV- vis spectroscopy is

usually applied to organic molecules and inorganic ions or complexes. The absorption of

UV or visible radiation corresponds to the excitation of outer electrons. There are three

types of electronic transition that can be considered for coordination compounds. The last

type of spectral of compound Cu(ii) complex of thiosemicarbazone is nuclear magnetic

resonance ( 1HNMR and 13CNMR) spectroscopy. The 1H and 13C NMR spectral data of

the ligands and copper (II) complexes are listed in Table 4 and table 5.

Table 4 shows 1H NMR spectral data (ppm) of the ligands and copper (II) complexes.

7
8
b. Main biological activity

The main biological activity for Copper (ii) - TSCs complexes is antiproliferative.

Copper is an important part of human proteins and enzymes. A small amount of copper is

needed by many important enzymes to participate and activate. Higher proliferation rate

in enzymes make the tumor cell require more copper than normal cell.

Thiosemicarbazone derivatives and copper have significant antitumor activity. (Qi et al.,

2020, #). For many decades, TSCs have been investigated for anticancer activity and

2-formylpyridine thiosemicarbazone (PT) was analyzed to have anti-leukaemic potential

which was led to further investigation of compound that was found to be an inhibitor of

DNA replication in sarcoma cells.

Due to the investigation, a role for Cu binding to thiosemicarbazone , the ligand

was found to be related with carcinostatic activity and based on the journals, recently the

new one ,Cu complex of thiosemicarbazone NSC689534 inhibited tumor growth in vivo.

(Duncan & White, 2011, #). Three Cu (ii) thiosemicarbazone complexes (C1-C3) were

synthesized and characterized. In order to evaluate the antiproliferative of Cu (ii)

complexes, the antiproliferative activity , the apoptosis analysis, intracellular reactive

oxygen species (ROS) and cell cycle was studied according to (Qi et al., 2020, #)

9
 Synthesis routes for C1-C3.

According to (rr) the in vitro antiproliferative activities of the copper(II)

complexes 1–3 and of the corresponding pro-ligands (H2L1, H2L2 and H2L3) were

evaluated against a panel of human tumor cell lines derived from solid tumors. The

cytotoxicity parameters, expressed as IC50 (the median growth inhibitory concentration

calculated from dose–survival curves), obtained after 72 hours exposure listed in table

below and cell lines representative of colon (HCT-15), lung (A549) and pancreatic

(BxPC3 and PSN-1) cancers, along with melanoma (A375), have been included

10
Mechanism of the biological activity of complex compound.

The mechanism starts with synthesizing the three ligands and three cu(ii)

complexes. Then, the structure of cu(ii) complexes was determined. All Cu(ii) complexes

were crystallized from methanol solution and their structure were identified by

single-crystal X-ray Diffractometer.

Molecular structure of cu (ii) complexes showing the environment about Cu atom.

[A=C1, B=C2, C=C3]

If ligands are similar in structure, the copper (ii) complexes differ in structure.

The C1 complex contains neutral thiosemicarbazone ligand and has square pyramidal

geometry while the other complexes contain anionic deprotonated ligand and crystallized

to square planar geometry. (Ramachandran et al., 2020, #)

Based on (Ramachandran et al., 2020, #) the scientists have studied the

thiosemicarbazone analogs and proved that Cu (ii) complexes of thiosemicarbazone have

significant antitumor activity. From the research, numerous reports indicate

thiosemicarbazone has significant activity against tumors such as liver and lung cancer.

The antiproliferative properties of the complex compound on two malignant cancer cell

11
(human lung cancer cell line, A549 and human colon cancer cell line ,Caco-2) were

evaluated and shown below :

The results showed that increases in lipophilicity of terminal-N substitution can

enhance the antitumor activity. The results after 48 hour of incubation shows that Cu(ii)

complex was higher than the corresponding ligands and C1 was similar to C3 and the

antiproliferative activity of copper complexes is determined by the corresponding

ligands, and the antitumor activity of the ligands is enhanced by coordination with

copper.

Next, to prevent the malignant proliferation of tumor cells, the cell cycle arrest

played the role and followed by cell apoptosis assay or the programmed cell death which

refer to the orderly death of the cell. Apoptosis is usually suppressed in tumor cells,

therefore activating it is an effective anticancer pathway. The result of cell apoptosis

proved that C3 has stronger ability to promote apoptosis.

12
 The intervention of some exogenous drug will cause excessive production of

reactive oxygen species (ROS) in cells that leads to apoptosis. Compared with the

control, the intracellular ROS of the three drug-treated cells were significantly increased,

and C3 had the strongest ability to promote the production of ROS. Excessive

intracellular ROS can inhibit G1, S, and G2 phase proliferation and combined with the

above-mentioned cell cycle analysis, it can be found that G2/M phase block is related to

antioxidative damage and antiapoptotic processes. (Qi et al., 2020, #)

13
c. Advantage and disadvantage of the complex compound of case study

Advantage of Cu(II) Thiosemicarbazone

As an essential trace element, copper is important for most living species,

involved in various kinds of important biological functions in cells, such as cellular

trafficking, substrate oxidation and redox regulation. Copper complexes of

thiosemicarbazone (TSC) provide a series of non-platinum compounds with antitumor

potential that are more efficient than cis-platin, a platinum-based anticancer drugs.

Copper complexes appear to have a mechanism of action different from that of

clinically used drug cisplatin because of its flexible Cu(I/II) redox behavior. It has been

found to be a more potent, clinically effective and less toxic antiproliferative agent. Some

studies showed that influx and efflux of platinum-based antitumor agents are also

regulated by transporters that control intracellular copper homeostasis. It probably strikes

the mechanism of resistance to platinum-based antitumor agents from the aspect of

transport system (Ma et al., 2014). Copper(II) can significantly propagate reactive oxygen

species (ROS) which further affects the development of cancer as well as the potential

manifestation of cytotoxicity. Copper was found to bind DNA with high affinity,

moreover higher than other divalent cations, thus promoting DNA oxidation. The binding

of copper ions to specific sites can modify the conformational structure of proteins,

polynucleotides, DNA, and biomembrane (Singh et al., 2020).

Thiosemicarbazones (TSCs) are a class of compounds that have a broad spectrum

of biological activity. In particular, their antitumor activity is often associated with metal

14
chelating ability, which controls the bioavailability of these metals. Moreover,

ligand-metal complexes are potential sources of free radicals. TSC complexation can also

affect important cellular processes such as cell cycle inhibition and the deactivation of the

ribonucleotide reductase (RR) enzyme. For example, 3-amino pyridine carboxaldehyde

thiosemicarbazone (3-AP), a well-known TSC member, is a potent ribonucleotide

reductase inhibitor that is the treatment of various tumors, including non-small-cell lung

cancer and renal carcinoma. In particular, this refers to a function of cancer cells (Ma et

al., 2014).

Organometallics, such as copper compounds, are cancer chemotherapeutics used

alone or in combination with other drugs. One small group of copper complexes exerts an

effective inhibitory action on topoisomerases, which participate in the regulation of DNA

topology. DNA topoisomerases have been molecular targets for anticancer agents.

Topoisomerases regulate DNA winding and play essential functions in DNA replication

and transcription. Copper complexes inhibitors of topoisomerases 1 and 2 work by

different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks

after the formation of a ternary complex, or act in a catalytic mode, often display DNA

intercalative properties and ROS production, and sometimes display dual effects. These

amplified actions have repercussions on the cell cycle checkpoints and death effectors.

Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view

and in the context of cancer cell mutations (Molinaro et al., 2020,).

15
 The following observations have been revealed for the anticancer potency of

copper(II) thiosemicarbazones such as the modification of N(4) position of the

thiosemicarbazones by cyclic ring such as piperidine, pyrrolidine etc increases the

anticancer activity. Next, replacement of the hydrogen atom at N(4) position of the

thiosemicarbazone by the electron releasing group increases its cytotoxicity. For example,

replacement of the terminal primary or secondary amino function by a tertiary amino

group resulted in a marked enhancement of cytotoxic activity. Unlike semicarbazone, the

thiosemicarbazones due to presence of sulphur atom have increased anticancer activity

(Singh et al., 2020).

Disadvantage of Cu(II) Thiosemicarbazone

Copper complexes can be highly toxic, can induce changes in cellular

metabolism, and can be rapidly taken up by cells, all of which can affect their ability to

function as catalysts for CuAAC in living systems. The mechanisms by which copper

inhibits or kills overloaded cells are not known. In studies of eukaryotic cells treated with

excess copper, people detected elevated levels of DNA lesions, protein oxidation, lipid

peroxidation, and reactive oxygen species generation. In vitro studies showed that copper

is capable of generating hydroxyl radicals from H2O2 and thereby facilitates oxidative

DNA damage (Macomber et al., 2007,).

Oxidative stress has more harmful properties than helpful ones. It can break down

cell tissue and cause a disadvantage which is DNA damage. This damage results in

inflammation thus leading to lifelong diseases-causing mutations like diabetes or cancer,

16
in some cases. Often associated with these copper(II) complexes is their instability in the

presence of strong cellular reductants such as ascorbic acid.

ROS-induced DNA damage products are both mutagenic and cytotoxic. Hydrogen

peroxide (H2O2), which generates hydroxy radicals in the presence of transition metal

ions, is considered an appropriate model for ROS. H2O2 is produced endogenously by

several physiological processes such as during oxidative phosphorylation and by the

inflammatory cell respiratory burst. Because it is freely diffusible, H2O2 can potentially

reach the nucleus to interact with DNA. H2O2 causes strand breaks and base damage in

DNA by a mechanism that requires transition metal ions, such as iron or copper.

Mixtures of Cu(II) ions and an oxidant like H2O2, often with the presence of

reductant such as ascorbic acid, generate ROS. These ROS produce extensive strand

breaks in DNA. Strand breaks often occur near guanine residues, and it has been

suggested that copper ions bind to DNA at these sites. Cu(II)/ascorbate/H2O2-mediated

DNA damage in aerobic aqueous solutions is believed to be induced in vitro and in vivo

through formation of a DNA–Cu(I)–H2O2 complex. DNA damage induced by

copper/H2O2 is enhanced by packaging of DNA into nucleosomes. ROS are generated

during inflammatory responses by neutrophils and phagocytes (Lee et al., 2002).

A variety of copper complexes with different structural features have been shown

to bind double-helical DNA with binding constants to promote double-strand DNA

damage upon reductant/H2O2 activation. The interaction of the Cu complex with DNA

17
results in hyperchromism and shifts to longer wavelengths of the strongest transitions in

the Cu complexes, as well as striking hypochromism or hyperchromism of DNA

absorption. The copper complex-mediated hydroxyl radical, a powerful oxidant that

attacks the adjacent DNA, is responsible for the DNA oxidative damage. The λDNA

damage chemistry illustrates that the competence and selectivity of double-strand λDNA

damage by the copper complexes are dependent on their geometric structures and types

of ligands.

These observations suggest that the structure of the copper complexes not only

governs DNA recognition, but also determines the DNA damage chemistry. The

identification of molecular structure which can efficiently and specifically perform DNA

double-strand cleavage, therefore, may be more general and important to consider in

understanding the reactions of DNA binding transition metal complexes (Liu et al.,

1999). Modification of thiosemicarbazones (TSCs) framework increases the

hydrophilicity or water solubility and decreases the toxicity of compounds.

18
d. Example of similar complex compound can be used for the chosen case study.

The similar complex compound that can be used for the chosen case study other

than Cu(II) thiosemicarbazone is Ni(II) thiosemicarbazone. The main reason is because

the interaction between these compounds and DNA has attracted great attention in

medicinal chemistry due to the potential use of these complexes as antineoplastic agents

(D. S. Kalinowski, Y. Yu, P. C. Sharpe, 2007). Next is, because of the pharmacological

potential of Cu(II) and Ni(II) thiosemicarbazone complexes and many researchers

showing interest in developing new molecules with biological activity A.

(Aragón-Muriel, M. Camprubí-Robles & E. González-Rey, 2014).

Based on the report presented by Polo-Cerón D (2019), new copper(II) and

nickel(II) complexes with tridentate thiosemicarbazone ligands 𝐻2 L1 and 𝐻2L2 derived

from 2-acetylpyrazine was synthesized. These compounds were characterized by

different physicochemical techniques and spectroscopic methods. Single crystal X-ray

diffraction studies revealed that, in the solid state, ligand 𝐻2L1 is present in the form of

thione, showing bond distances which reveal charge delocalisation between the atoms of

the thiosemicarbazone group. To evaluate the potential biological activities of the

synthesized compounds, studies on their DNA interactions and antibacterial activities

were performed. The results obtained from the electronic absorption spectra, viscosity

measurements, and oxidative cleavage reactions showed that complexes 1–4 can

efficiently interact with DNA strands. The antibacterial activity assays showed that the

complexes have concentration-dependent bactericidal activities, and the best results were

19
obtained for copper complexes 1 and 2 with MIC values of 3.9 μg·mL−1 for S. aureus

and B. cereus strains.

In short, these results are promising and contribute to ongoing studies on the

mechanisms of action of coordination complexes, and these results will inspire research

on the design of new and better metallodrugs containing this kind of ligands.

20
CONCLUSION

In the final analysis, we learned the fundamental role of metal ion copper(II) and the

recognition of its complexes as important bioactive compounds in vitro and in vivo aroused an

ever-increasing interest in these agents as potential drugs for therapeutic intervention in various

diseases as well as its application in daily life. We get to know that thiosemicarbazone is well

known for their broad spectrum of biological activity and has numerous forms that can be

synthesized for anticancer properties. As for the coordination compound chosen, Cu(ii)

complexes of thiosemicarbazone have an antiproliferative activity which is similar to antitumor

activity in which it inhibits cell growth which is good to kill the tumor cell. In other word, we

can concluded that these coordination compound play an important role in our life especially the

fight against infectious diseases, one aspect of this field, has seen great advances via multiple

investigations have been performed to test new free organic or metal coordination compounds,

which can be precursors of more efficient and less toxic drugs by acting through different

biological mechanisms. The vast array of information available for their bioinorganic properties

and mode of action in several biological systems, combined with the new opportunities offered

by the flourishing technologies of medicinal chemistry, is creating an exciting scenario for the

development of a novel generation of highly active drugs with minimized side effects which

could add significantly to the current clinical research and practice.

21
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