INTRODUCTION:

A. BACKGROUND
Leukemia is a cancer that begins in bone marrow. Usually, leukemia involves the
production of abnormal white blood cells which is the cells responsible for fighting
infection. The abnormal cells do not function correctly. The leukemia cells continue to
grow and divide, eventually crowding out the normal blood cells. The end result is
that it becomes difficult for the body to fight infections, control bleeding, and transport
oxygen. (von Bubnoff & Duyster, 2010)

There have four common types of leukemia which is acute lymphocytic leukemia
(ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic
lymphocytic leukemia (CLM). While no one knows exactly what is causes leukemia,
but there have some factors that are increase risk of the certain leukemia. People
are likely to get leukemia if they undergo certain type of chemotherapy, exposure to
radiation and hazardous chemical like benzene and if they have genetic problems
such as Down syndrome. This cancer mostly infects both children and adult
especially men. There are around 54,000 new cases of leukemia each year in the
U.S. and about 24,000 deaths due to leukemia. Leukemia makes up about 3% of all
new cancer cases. (Stoppler & Balentine, 2016)

Many treatments can be applied to cure leukemia such as chemotherapy,

radiation therapy, biological therapy, targeted therapy and stem cell transplant.
However, there is one newest treatment that has been circulating in the medical field
these days

which is by using anti-cancer agent. The agent is Nickel (II)

thiosemicarbazone complex that can act as an anti-cytotoxic agent. The complex

was prepared by substituting 3-methoxy and 4-hydroxy in N1-salicylidene-Smethylisothiosemicarbazone corresponding aldehyde in the presence of nickel
chloride NiCl. (Bal-Demirci, et al., 2015)

B. OBJECTIVES
There have two complexes formed from reaction that have different position of
methoxy and hydroxy. So, infrared spectra and 1H-NMR spectra were used to detect
the functional group and number of hydrogen in the complexes. Only one of the
complexes can act on leukemia cells line effectively.

The objective of this assignment is to investigate biological activity and

mechanism of the Nickel (II) thiosemicarbazone which acts as cytotoxic agent
against leukemia cells. The other purpose of this assignment is to find the
effectiveness of the Nickel (II) complexes toward the cancer cells. Nickel is a metal
ion that harms human biological system and is cancerous. However, it can bind with
thiosemicarbazone complex to become anti-cancer agents such as other metal ion
for example: iron, zinc and copper. (Zhang, Li, Chen, Wang, Ye, & Ji, 2014)

C. PROBLEMS
There is some problem that has occurred while writing the report. Most of the
references used medical jargon that causes difficulty for us to understand. Journal
authors used many short form of word and they also used high level English
languages that are suitable for Ph.D scholars. To overcome the problems, we need a
lot of references to understand the meaning behind their research. However, we

encounter new problem while searching for references as our title of assignment is a
new research of study.

D. SCOPE AND SOURCES

The scope of the report is based on the biological system and chemical
interaction between Nickel(II) complex towards DNA to treat cancer and tumorous
cells. The sources of the references are from medical, pharmaceutical, chemical,
and biological journals. The other sources are from books from the library and
medicinal article from internet about the current issue of leukemia.

E. PERSONAL OPINION
In our opinion, biological problems that can cause harm to human body such as
cancer can be treated by using proper chemical that can have an interaction to the
DNA in cells. This can reduce cost of treatment of cancer patients and also reduces
the time taken to treat the cancer cells compared to the other treatments that is
available nowadays. Based on our reading for this assignment, metal ions have the
property to destroy cancer cells and can give importance to biological system of
human body especially in cancer cells.

LITERATURE REVIEW:
A. COMPLEX COMPOUND:
i. BIOLOGICAL IMPORTANCE
The thiosemicarbazones consist great significant which it have more donor
atom and the type and position of substituent on thiosemicarbazones, type and
charge of metal atom shows their variable behaviours of metal complexes. They also
stated the elemental analysis, IR, 1H NMR, ESR spectral analysis, and molar
conductance were characteristic of the Schiff base and metal complexes. Moreover
other researchers study indicated these ligands are strongly coordinating agent and
form stable complexes with various transition metal ions. They also found these
ligand biological activities developed with the complexation with metal ion and
reacted selectively with certain biological system. (Premlata, Verma, & Seth, 2012)

The concern toward coordination chemistry continuously develop with the

synthesis and characterization of immense transition metal complexes with
heterocyclic ligands containing nitrogen, oxygen, sulphur donors. According to (BalDemirci, Sahin, Kondakci, Ozyurek, Ulkuseven, & Apak, 2015) usually the transition
metals behave a very important function in an organism and their complexes can
interact non-covalently with nucleic acid by intercalation, groove-binding or external
electrostatic binding for cations. They highlighted the nickel(II) complexes of Smethylthiosemicarbazones have efficient cytotoxic activities for leukemia cells and
may show remarkable therapeutic drug potential due to their cytotoxicities at 15 M
against K562 cells (Chronic Myeloid Leukemia).

As expected by having wide-spectrum biological activity of thiosemicarbazone

derivatives that synthesis researchers made, the benefit on these compounds has
been considerably boost in the pharmaceutical sector at the present time.

Moreover, complex 2 proficient to inhibiting the growth of the cancer cell lines
tested which has a distorted square planar environment with L acting as a bidentate
NS-donor ligand. The antiproliferative, antibacterial, antitumor, antifungal and
antileukemic properties are the wide range of biological activities well known as their
derivatives of thiosemicarbazones and their metal complexes. (Bal-Demirci, et al.,
2015)

It is highly desirable in order to maximize the delivery of the anticancer agent

into the cell and onto the DNA by targeting the drugs to a specific organ or tumour
type. By applying drug carrier strategy instead of free drug solution it also can be
achieved. While minimizing toxicity to healthy cells, drug carrier systems are able to
protect the cytotoxic agents against elimination and in vivo degradation, thereby
conveying the drugs to the target. (Bal-Demirci, Sahin, Kondakci, Ozyurek,
Ulkuseven, & Apak, 2015)

Free radicals are highly reactive compounds and at high concentrations it can
damage all components of cells such as DNA, proteins, cell membranes. According
to (Heng, et al., 2015), in order to retard autoxidation and neutralize free radicals
associated with the development of cancer and other health problems, the
antioxidants is used. The free radical scavenging activity thiosemicarbazones and
their metal complexes have been evaluated in their studies.

ii.

PREPARATION AND CHARACTERISTIC

Synthesis of thiosemicarbazones:
3-Methoxy-(LI)

and

methylisothiosemicarbazones

4-hydroxy-(LII)
were

synthesized

substituted-N1-salicylidene-Sfrom

the

corresponding

salicylaldehyde (1 mmol), methyl iodide (1 mmol) and thiosemicarbazide (1g, 1mmol)

in equimolar ratios according to the literature. The compounds were checked using
elemental analysis and characteristic spectroscopic data. The colour, yield (%),
melting point (C), elemental analysis, IR (KBr, cm -1) and 1H-NMR (DMSO-d6, 25
1C, ppm) data of L1 and LII are given as follows:

a) LI: cream, yield (1.552 g, 93%), 164165 1C.

Anal.calc. for C10H13N3O2S (239 g mol-1):C, 50.21; H, 5.44; N, 17.57; S, 13.39, found:
C, 50.25; H, 5.42; N, 17.56; S, 13.40%.
IR: va(NH) 3412, vs(NH) 3306, v(OH) 3129, (NH) 1651.
NMR: 11.58, 10.71 (cis/trans ratio: 2/1, s, 1H, OH), 8.44, 8.30 (syn/anti ratio: 2/3, s,
1H, CH=N1), 6.84 (s, 2H, NH2), 2.42, 2.37 (cis/trans ratio: 3/2, s, 3H, SCH3), 3.77 (s,
3H, OCH3).

b) LII: pinkish cream, yield (1.425 g, 94%), 179180 1C.

Anal.calc. for C9H11N3O2S (225 g mol-1):C, 48.00; H, 4.89; N, 18.66; S, 14.22,
found: C, 48.18; H, 4.92; N, 18.66; S, 14.27%.
IR: va(NH) 3445, vs(NH) 3337, v(OH) 3495, (NH) 1624.
NMR: 11.67, 11.02 (cis/trans ratio: 5/2, s, 1H, OH), 9.75 (s, 1H, OH), 8.32, 8.20
(syn/anti ratio: 2/3, s, 1H, CH=N1), 6.71, 6.65 (syn/anti ratio: 1/1, s, 2H, NH2),2.42,
2.38 (cis/trans ratio: 3/2, s, 3H, SCH3).
6

For the synthesis of complex 2, compound L I (1.0g,1mmol) and 2,4dihydroxybenzaldehyde (0.58 g,1mmol) were dissolved in 25 mL of ethanol. The
mixture was added to a solution of 1.70 g (1.5mmol) NiCl 2.6H2O in ethanol (25mL)
and then 10mL of triethylamine. After 24 h, the black precipitate was filtered off,
washed with ethanolether (1 : 1, 10 mL) and dried in vacuo over P 2O5.

The colour, yield (g, %), melting point (C), molar conductance (Ohm -1 cm2
mol-1, in 10-3 M DMSO, 25 C), eff (BM), elemental analysis, IR (KBr, cm -1), 1HNMR (DMSO-d6, 25 C, ppm) and (+) ESI-mass data of the complexes are given
as follows:

Figure 1: The compounds. R1: 3-OCH3 (Li), 4-OH (Lii); M/X/R1/R2: Ni//3-OCH3/4-OH

Complex 2: red, yield (0.6080 g, 35%), 276277 (decompose) C, 6.45, 0.06.

Analysis Calculation for C17H15N3O4SNi (415.7 g mol-1): C, 49.07; H, 3.63; N, 10.10;
S, 7.71,
found: C, 49.05; H, 3.68; N, 10.34; S, 7.85%.
IR: v (OH) 3445, v (C=N) 1608, 1594, v(CO) 1150, 1112.
NMR: 10.85 (s, 1H, OH), 8.42 (s, 1H, CH=N 1), 7.97 (s, 1H, CH=N4), 6.30 (dd, J =
8.69, J = 1.83, 1H, b), 6.55 (t, J = 7.78, 1H, c), 7.58 (d, J = 8.69, 1H, d), 6.26 (s, 1H,
p), 6.85 (d, J = 7.77, 1H, r), 7.10 (d, J = 8.24, 1H, s), 3.74 (s, 3H, OCH3), 2.69 (s,
3H, SCH3)

Cell cultures:
The K562 chronic myeloid leukemia cell line was purchased from ATTC. In
addition, mononuclear cells (MNC) were isolated from normal human peripheral
blood using Histopaque 1077. The cells were cultured in IMDM (for K562 and MNC)
8

media (Sigma) supplemented with 10% fetal calf serum (GIBCOBRL) and 1%
penicillinstreptomycin. Experiments were conducted on cells seeded into 96-well
culture plates at densities 105 cells per mL while maintaining the cells at 37 C in an
atmosphere of 5% CO2 in air.

Results and Discussion:

Thiosemicarbazones LI and LII are soluble in methanol, ethanol, and
chlorinated hydrocarbons. The reactions of LI and LII with corresponding aldehydes in
the presence of iron(III) and nickel(II) in the 1 : 1 : 1 molar ratio yielded solid

complexes. The complexes are very soluble in donor solvents such as

dimethylformamide and dimethyl sulfoxide, but less soluble in ethanol and
dichloromethane. The solid complexes are stable for several weeks in air. The
thiosemicarbazones and complexes are in the form of very fine powder crystals.

The meff values of iron(III) complexes 2 that are in the 5.865.88 BM range
are equivalent to five unpaired electrons and so the iron(III) ion is in the high-spin
state indicating the [Fe(L)Cl] structure. Magnetic measurement results of nickel(II)
complexes 2 showed that they are diamagnetic and have a square-planar structure.
Template reactions of the thiosemicarbazones and aldehydes can be easily
monitored by means of IR and 1HNMR spectra. The (NH2) bands disappeared in
the infrared spectra of the complexes due to reactions of 2-hydroxy and thioamide
groups.

The protons of starting materials LI and LII showed the expected chemical shift
values, and even the systematic signals of synanti and cistrans isomers. In the
NMR spectra of complexes 2, the proton signals of 2-OH and N 4H2 groups were
absent because of chelation. Besides, the arising N 4=CH signal which is a singlet
and equivalent to the integral value of one proton confirms the chelate formation
around nickel(II).
The analytical and spectral data provide evidence that the chelating N 1,N4disalicylidene-S-methylisothiosemicarbazida to ligands bonded through the O,N,N,O
donor set has been previously accomplished.

B. MAIN BIOLOGICAL ACTIVITY AND MECHANISMS

10

Based on numerous distinctive medical terms, cancer is characterized by

abnormal growth due to spontaneous, inherited or environmentally induced genetic
mutations. (Sanyal, Dash, Kundu, Mandal, Roy, & Das, 2016)

Recently, the leading role of the 3d transition metal ions on the conformational
arrangements of the genetic material at the subcellular level plays an important role
in the regulation of genome activity and becoming significantly evident. (Sigel &
Sigel, 1988)

Based on the main journal article, complex 2 acts by inhibiting ribonucleotide

reductase (a key enzyme in the biosynthesis of DNA precursors). The presence of
bulky group at N(4) of the thiosemicarbazone moiety enhances the antitumor
activities. Coupling of Nickel(II) ions which is mutagenous that is present in the
complexes to the DNA exhibited significant antitumor activity of their parent ligand,
which leads with some probability to tautomeric base changes. This in turn causes
changes in the double helix stability and leads to various defects of its structure.
(Sigel & Sigel, 1988)

Thiosemicarbazone exert cytotoxicity activity via induced loss of mitochondria

membrane potential (MPP). Mitochondria was considered to be a major site of
antitumor agents through electron leakage from the electron transport chain, the
decreased MPP may open the mitochondrial permeability transition (MPT) and
trigger the release of Cytochrome C which activate caspase cascade, causing cell

11

death. Common process of programmed cell death in the human body is called
apoptosis.

The complex inhibits tumour cell growth against K562, the site for the
development of Chronic Myeloid Leukemia (CML) cell line due to the NNS (NickelNickel-Sulphur) tridentate system. (Pape, et al., 2016) The number of cells that
undergone apoptosis were increased in a concentration-dependent manner
companying decreased MPP after incubation with the tested compounds for 24
hours, indicating the remarkable antitumor activity in vitro. (Li, Zhang, Zhang, Ji, &
Zhao, 2011)

Cell viability studies highlight potent anti-leukemic activity towards K562

(Chronic Myloid Leukemia) cell lines. Anti-bacterial property was investigated upon
multi-drug resistant E. coli and S. aureus bacteria to illuminate the versatility of nickel
biology.

12

Figure 2: Anti-bacterial sensitivity pattern of complex by disc agar diffusion method.

A: Graphical representation of diameter of inhibition zone.
B: Disc agar diffusion pattern of multi drug resistant E. coli strain.
C: Disc agar diffusion pattern of multi drug resistant S. aureus strain.

All strains were exposed to 20L of only DMSO solution (a) and 25g (b), 50g (c),
100g (d), 200g (e) and 400g (f) complex dissolved in DMSO solution containing
disc and subsequently incubated for 24 hour at 37C. Inhibition zones were recorded
by using zone scale. Values are expressed as mean of three separate experiments; *
and # indicates significant difference (p < 0.05) compared to the control group.

13

The cytotoxicity of the complex was quantitatively estimated by a nonradioactive colorimetric assay using tetrazolium salt (MTT). The complex showed
dose responsive cytotoxicity against lymphocyte. Potent anti-leukemic effect was
observed upon both the cell lines. The complex selectively killed the leukemic cells
by generation of reactive oxygen species (ROS) which activated several downstream
signalling pathways leading to cell death by apoptosis.

Activation of endogenous nuclear endonuclease selectively and distinctively

cleaves the double-stranded nuclear DNA. Thus elevated level of ROS may
contribute to severe genotoxic effects in leukemic cell lines. Most of the cells
exhibited typical characteristics of apoptotic cells like plasma membrane blebbing
which happens when the cell detaches its cytoskeleton from the membrane, causing
the membrane to swell and distorting the shape of the cell. Most of the leukemic cells
were not undergoing necrosis and cell death occurred primarily through apoptosis.
Novel complex depicted potent in vitro anti-proliferative activity against K562 cell
lines. These promising results are essential for antibacterial and anticancer drug
development in the medical field. (Sanyal, Dash, Kundu, Mandal, Roy, & Das, 2016)

14

C. ADVANTAGE AND DISADVANTAGE

Metal-containing compounds offer many advantages over conventional carbonbased compounds in the development of new medicinal compounds. These
advantages are due to their ability to coordinate ligands in a three dimensional
configuration, thus allowing functionalization of groups that can be tailored to defined
molecular targets. Metal-based complexes offer a rich environment to build upon a
variety of distinct molecular structures that confer a wide spectrum of coordination
numbers and geometries, as well as kinetic properties, that cannot be realized with
conventional carbon-based compounds. (Arora, Agarwal, & Singhal, 2014)

The partially filled d orbitals in transition metals impart interesting electronic

properties that can act as suitable probes in the design of anticancer agents. The
oxidation state of a metal is also an important consideration in the design of
coordination compounds, given that it allows the participation in biological redox
chemistry and plays an influential role in optimal dose and bioavailability of the agent
administered. (Frezza, et al., 2013)

The disadvantage in the use of anticancer compounds arises from adverse

toxicity to non-targeted tissues. This is because most anticancer drugs were
discovered based on their efficacy against cancer cells; little attention was initially
given to their effects on other tissues. (Cheung-Ong, Giaver, & Nislow, 2013)

15

D. EXAMPLE OF SIMILAR COMPLEX COMPOUND

Figure 3: A view of complex 1 showing the atom-numbering scheme. Displacement ellipsoids

are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary
radii. Hydrogen bonding interactions are indicated by dashed lines.

Iron (III) and Nickel (II) exhibit the same properties as a cytotoxic anticancer
agent against leukemia. The complexes may very likely be potential anticancer drugs
due to their ability of binding to DNA and show a cytotoxic effect at very small
concentrations

in

cell

cultures.

Iron

(III)

is

composed

of

an

N1-3-

methoxysalicylidene-N4-4-hydroxysalicylidene-S-methylisothiosemicarbazidato
chelate with an Fe(III) metal centre and one Cl ligand, and crystallizes with a solvent
water molecule in the asymmetric unit.

16

Iron(III) affects cell proliferation and induce apoptosis in leukemia cells.

Importantly these authors also demonstrated that Iron(III) kills even drug resistant
leukemia cells and primary leukemia cells more efficiently than conventional
chemotherapeutic drugs indicating potential application of Iron(III) complex towards
treatment of leukemia. Iron(III) not only interact with free DNA in vitro but also induce
nuclear condensation, fragmentation and apoptosis in cultured cells in vivo. Iron (III)
affect mitochondrial membrane potential, induce cytochrome-c release from
mitochondria to cytosol, and induce caspase activation indicating mitochondrial
pathway of apoptosis. (Dash, et al., 2013)

The antitumor activity of iron(III) complexes in vitro and ex vivo against

leukemia cells. These studies demonstrated that iron(III) induced efficient apoptosis
in leukemia cells and has the ability to overcome multiple drug resistance in
vincristine and daunorubicine resistant leukemic cells.

The impact of iron(III)

complex in primary myeloblasts isolated from bone marrow aspiration of children

with relapsed all or primary aml and these studies revealed a higher sensitivity of
these tumor cells towards iron(III) treatment in comparison to conventional cytotoxic
drugs.

According to (Deo, Pages, Ang, Gordon, & Aldrich-Wright, 2016), Iron(III) is

capable to overcome resistances against vincristine and daunorubicine that are
commonly used for treatment of leukemia. Mechanistic studies demonstrated that
treatment with iron(III) results in loss of mitochondrial membrane potential in
lymphoma cells, and up- and downregulated various genes associated with apoptotic
cell death suggesting involvement of mitochondrial pathway of apoptosis.

17

Both Iron (III) and Nickel (II) shows decrease in oxidation signal and increase
in adenine signal. They affected the double stranded DNA structure and adenine in a
concentration dependent manner. The meff values of iron(III) that are in the 5.86
5.88 BM range are equivalent to five unpaired electrons and so the iron(III) ion is in
the high-spin state indicating the [Fe(L)Cl] structure.

The compositions of paramagnetic iron(III) complexes, [Fe(L)Cl]HO, justify

[MCl] peaks as well as other mass data. Meanwhile, magnetic measurement results
of nickel(II) (Complex 2) showed that they are diamagnetic and have a square-planar
structure. The Iron(III) complex have geometries ranging from square-pyramidal to
trigonal-bipyramidal. In the case of an ideal square-pyramidal geometry,the t value is
equal to zero, while it becomes unity for a perfect trigonal-bipyramidal geometry.
(Khan, Ahmad, Joshi, & Khan, 2015)

The value of t for the FeIII ion is 0.05, indicating a slightly distorted squarepyramid. In the square-pyramidal geometry, the basal plane defined by the two N
and two O atoms of the Schiff base ligand and the apical position occupied by a
chloride ligand. Atom Fe1 is 0.511(2) above the best plane defined by the Schiffbase N and O donor atoms. In a conclusion possession of an hydroxy substituent
cause an increase in cytotoxicity. Therefore both complex have similar properties
and can also be used as a cytotoxic agent against leukemia. (Jyothi, Farook, Cho, &
Shim, 2013)

18

Figure 4: Immunohistochemistry results of the caspase-3 protein expression after 72 h

treatment with Iron(III) complexes in leukemia cells. The brown colour represents a positive
staining of caspase-3. A control cell was prepared without complexes and represents a
negative staining.

CONCLUSION:
Based on the results presented in the entire journal articles, the key
mechanism of the transformation of tumorous cells is the DNA damage as a result of
mutation. However, if it is bind to the 3d transitional metal such as Nickel(II) it can act
as a cytotoxic agent against cancer cells. Biological activity and mechanism of the
Nickel (II) thiosemicarbazone which acts as cytotoxic agent against leukemia cells
was investigated and the effectiveness of the Nickel(II) complexes toward the cancer
cells was proven.

The results obtained from the MTT assay showed that the cytotoxic effect of
the Nickel(II) thiosemicarbazone are cytotoxic against K562 leukemic cells. In
addition, the percentage of DNA fragmentation and caspase 3 expression was
decreased indicating cytotoxic effect caused by triggering the apoptotic pathway.
Apoptosis is a programmed cell death and cell necrosis does not occur. (Mandal,
2012)
19

The interaction mechanisms were evaluated in terms of the increase and

decrease in the oxidation signals of the compounds and electro active bases of DNA
of E. coli and S. aureus. There was a strong evidence that complex 2 affected the
double stranded DNA structure in a concentration dependent manner.
Moreover, nickel(II) thiosemicarbazone has a selective antileukemic effect and
drug potential. We believe that the complexes may very likely be potential anticancer
drugs due to their ability of binding to DNA and show a cytotoxic effect at a very
small concentration in cell cultures.

20

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