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Synthesis of New Platinum-Based Anti-Cancer DrugsMaster's Theses
Graduate College
Saud O. Albaroodi Yasser
Part of the Chemistry Commons
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O., "Synthesis of New Platinum-Based Anti-Cancer Drugs" (2015).
Master's Theses. 618.
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by
Yasser Saud.O Albaroodi
A thesis submitted to the Graduate College in partial fulfillment
of the requirements
for the degree of Master of Science Chemistry
Western Michigan University August 2015
Thesis Committee:
Ekkehard Sinn, Ph.D., Chair Ramakrishna Guda, Ph.D. Sherine Obare,
Ph.D.
SYNTHESIS OF NEW PLATINUM-BASED ANTI-CANCER DRUGS
Yasser Saud.O Albaroodi, M.S.
Western Michigan University, 2015
Cancer is considered the second leading cause of death after heart
attack. Different treatments have been applied to kill cancer cells
such as chemotherapy, which is the use of chemicals or drugs in
order to treat cancer cells. Platinum-based anti cancer drugs are
the backbone of chemotherapy, they play a crucial role in treating
various malignant tumor. However, the disadvantages of these drugs
are very painful on patients, such as nephrotoxicity and
ototoxicity. In the last four decades, thousands of platinum-based
anticancer drugs have been synthesized for hope in find a new drug
with higher efficacy and less side effects.In this study, three
different types of platinum-based anticancer drugs are considered.
The first type, chelate agents, which provides stability and force
the drug to form with cis configuration. Five out of six of the
approved platinum-based anticancer drugs have bidentate ligands,
which proves the advantages for synthesis of new drugs with
bidentate amine ligands. The second type, Pt(IV)-based complexes,
which is an active field due to the benefits that octahedral
complexes provide. None of Pt(IV) drug has been approved, however;
three drugs are undergoing clinical trail. This field is quite
interesting for further investigations. The third type, π-bond
binding, whihc is a new study of organic couplings that can bind to
metal center by the pi bond instead of the nitrogen, this new
feature can lead to a new field where it can be used for anticancer
drug, or by inhibiting COX enzyme, the enzyme that causes pain.
Fiver differentt drugs have been synthesized, and they are
DPAPlatin, PhenPlatin, TriPicolyAminePlatin, DiPhenPlatin, and
DCCplatin.
ACKNOWLEDGEMENTS
This study is in a memory of my grandparents who suffered from
cancer.
This project would not have been possible without the support of
many people who have been helping me out through all
circumstances.
Special thanks to my advisor, Dr Ekkehard Sinn, who read my
numerous revisions and helped make some sense of the confusion, who
has given me all the support any graduate student needs.
I would have never been able to finish this work without the
support of friends from chemistry department, Viraj Dhanushka,
Agozie Oyeamalo, Joseph Kreft, Wesam Alisawi, Sarah Albalawi, Sarut
Jianrattanasawat, David Sellers and Hazim Alzubaidi.
Also billion thanks to my committee members, Dr Sherine Obare and
Dr Rakarishna Guda who offered guidance and support. Thanks to
Western Michigan University for giving me the opportunity to pursue
masters degree. Many thanks to the Saudi Arabian Cultural Mission
for providing me with the financial means to complete this
project.
In order to achieve this, I have needed a lot of supports. As I
have been through ups and downs, I needed pure people who I can
rely on, some friends who could support me. Honestly, I have come
to realize that being around successful people leads you to
success, and here I would love to thank my successful friends, Anas
Justanieah, Hadeel Bogary, Haitham Alshaebi, Omar Bajamal,
Abdulelah Bajammal, Abdulgader Almkkawi, and Noran Alahdal. Cannot
forget my parents, Saud and Zaka, and my siblings, Mohammed; Osama;
Abdulrazag; and Dana who hasve shown me how to be successful in my
life. My relatives, who showed me love and support in a way that
encouraged me to work hard.
And my wife, Susana, the one who has given me all the help and
support, she has been by my side through thick and thin, without
her, I don’t really think I would be able to achieve this. Her
parents and siblings that were such a great family to me.
Thank you all for everything, for all the support, for all the
help, for all the love.
Yasser Saud.O Albaroodi
1.1.3. Side effects of platinum-based
drugs……………………………………………….3
1.1.4. Platinum-based complexes………………………………………………………….3
1.2.1. Platinum complexes and nitrogen-donor
ligands……………………………………6
1.2.2. History of platinum-based drugs…………………………………………………….7
iii
1.3. Pt(IV)-based complexes…………………………………………………………………..9
1.3.1. Structure activity……………………………………………………………………10
1.4. Attaching metal center to π-bond of organic
compound.………………………………..10
1.5. Objectives of the study…………………………………………………………………..11
1.6. References……………………………………………………………………………….12
2.1. Introduction………………………………………………………………………….…..17
2.3.4. Characterization of DiPhenPlatin………………………………………………….37
iv
Table of Contents - continued
2.4. References……………………………………………………………………………….42
3.1. Summary……………………………………………………………………………….43
3.2.2. More of platinum (IV) anticancer
drugs…………………………………………..52
3.2.3. Tethering carboxylic acid…………………………………………………………53
3.3. References……………………………………………………………………………..54
2. Approved platinum-based anticancer
drugs…….………………………………………………6
3. Mechanism of action of cisplatin………………………………………………………………8
4. Pt(IV)-based complexes that are going under clinical
trail…………………………………….9
5. Proposed mechanism of action of chelate
agents……………………………………………..18
6. A possible breakout that can lead to two different drugs of
PhenPlatin………………………19
7. The octahedral geometry of Pt(IV)-based
complexes…………………………………….…..20
8. Proposed mechanism of action of Pt(IV)-based
complexes…………………………………..21
9. Zeies’s salt…………………………………………………………………………………….22
10. The mechanism of the synthesized drug
“DPAPlatin”………………………………………23
11. The mechanism of the synthesized drug
“PhenPlatin”………………………………………24
12. The mechanism of the synthesis of the synthesized drug
“TriPicolyAminePlatin”…………25
13. The mechanism of the synthesized drug
“DiPhenPlatin”……………………………………26
14. The mechanism of the synthesized drug
“DCCPlatin”………………………………………27
15. The synthesized platinum-based anticancer drugs under “chelate
agents” category………..45
16. Views of Cu(phen)2+/DNA…………………………………………………………………46
17. The synthesized platinum (IV)-based anticancer
drugs……………………………………..48
18. Design and reactivity of potassium [2-(prop-2-enol)-2-ace
toxybenzoat]trichloroplatinate(II)
(Pt-Propenol-ASS)……………………………………………….………………………………50
19. DCCPlatin that has the platinum attached to the π-bonds of N,N
dicyclohexylcarbodiamindichloro………………………………………………………………..51
vi
ER………………………………………………………………………………..Estrogen receptor
INTRODUCTION
1.1.Cancer
A universal health concern, that is the main reason of
approximately 13% of all types of hu- man deaths around the world,
is cancer. Even though noteworthy processes have been studied,
including chemotherapy, there is a significant increase in cancer
diagnosis; around 25 million of the world population are suffering
from this devastating disease [1]. The antitumor drug, cis- platin,
figure 1, discovered in the 1960s, has become one of the most
useful agents to treat differ- ent types of cancer [2]. Nowadays,
it has been used in over 50% of cancer treatments [3]. Over 100
drugs have been studied, tested and used to date in chemotherapy.
Drugs are used based on specific kinds of cancer. By reason of
their cytotoxic activity, platinum and its derivatives play an
important role in anti-tumor drugs, and cisplatin can be a very
useful prototype [4]. However, cisplatin has major side effects
which have reduced the efficacy of using it. These include
nephrotoxicity, myelotoxicity, neurotoxicity, nausea, and vomiting,
as well as harming healthy cells due to insufficient specificity in
targeting of tumor cells [5]. All those drawbacks have been an
incentive to scientists to overcome them with better solutions
which would not affect healthy cells.
Figure 1. Cancer statistics in the U.S. in 2015.
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1.1.1. Cancer treatment
There are many factors to determine cancer treatment including the
stage of the cancer, the size of the tumor and finally whether it
is just a tumor or metastatic cancer. Depending on all the previous
concepts, cancer treatment would be one or more the following:
surgery, hormonal ther- apy, immunotherapy, radiation treatment,
and chemotherapy [6,7].
1.1.1.1 Surgery
Surgery is one of the cancer treatments which relies on removal of
the cancerous cells and tis- sues. Surgery might require other
treatment such as chemotherapy or radiation treatment in order to
eliminate residual cancer cells, decrease the scale of the tumor or
to prevent the cancer from growing, spreading or re-occurring
[8].
1.1.1.2 Hormone therapy
Blocking estrogen from the estrogen receptor, ER, is how hormone
therapy functions, or even by preventing estrogen from
bio-synthesizing itself. It is recommended for ER+ breast cancer
cases [9,10].
1.1.1.3 Immunotherapy
Various studies have hinted at the capability of the immune system
to attack the protein that supports the growth of cancer cells
[11].
1.1.1.4 Radiation therapy
Due to its high energy, radiation treatment can kill cells by
damaging their DNA. It has been used for more than 20 years and its
function is to kill cancer cell by targeting them with the radi-
ation beam. However, the difficulties of targeting just the tumor
cells without damaging some healthy cells are limitations to its
use [12].
1.1.1.5 Targeted therapy
As previously mentioned, poor selectivity and specificity are
drawbacks in chemotherapy; studies have been carried out in order
to make improvements, and that has led to drug targeting delivery,
DTD. Due to its avoidance of damaging normal cells and the
restraint drug resistance, DTD represents a very promising step
which has been called ‘magic bullet’. The main reason of
!2
these endeavors is to develop platinum drugs that are significantly
selective for tumor cells and can be administered at lower doses
with fewer side effects and an improved therapeutic index
[13].
1.1.1.6 Chemotherapy
Chemotherapy means using chemicals or drugs to treat a disease. In
the case of cancer, it means to use drugs in order to kill the
cancer cells, and when possible to kill them selectively
[14].
1.1.2 Approved platinum-based drugs
According to US the Food and Drug Administration, FDA, several
cancer drugs have been ap- proved in 2014. Listed below are the
names of the approved cancer drugs in 2014, and a there are a lot
more from previous years. The approved cancer drugs are
Pembrolizumab, bevacizum- ab, idelalisib, belinostat, ceritinib,
mercaptopurine, siltuximab, ramucirumab, ofatumumab, ibru- tinib,
and trametinib [15].
1.1.3 Side effect of platinum-based drugs
Unfortunately, cancer drugs are generally not selective, which
means they attack healthy cells as well as cancer and tumor cells.
The pain that they leave, as well as the long period of time of
treatment, which can take up to five years, actually cause some
people to give up on the treat- ment. Various side effects might
occur such as nephrotoxicity, myelotoxicity, neurotoxicity, nau-
sea, and vomiting. The current studies are made in order to obtain
a safer drug delivery with low- er toxicity and higher selectivity
[16].
1.1.4 Platinum-based complexes
Platinum-based anticancer drugs occupy a crucial role in the
treatment of various malignant tumors. However, the efficacy and
applicability of platinum drugs are heavily restricted by se- vere
systemic toxicities and drug resistance. Different drug targeting
and delivery (DTD) strate- gies have been developed to prevent the
shortcomings of platinum-based chemotherapy [13]. Platinum (II)
complexes are commonly used in cancer chemotherapy [17].
“Classical” Pt(II)- drug complexes[18,19] are cisplatin (trade
names Platinol and Platinol-AQ), carboplatin, oxali-
!3
platin, nedaplatin, lobaplatin, and heptaplatin. Cisplatin is one
of the most potent antitumor drugs against solid tumors, such as
ovarian, testicular, lung, head, neck, and bladder cancers [20].
Its anticancer activity results from the formation of stable DNA-Pt
complexes through intra-strand cross-links, resulting in alteration
of the DNA structure, which prevents replication and favors
initiation of apoptosis. Cisplatin is unstable in water with a
first hydrolysis half time t1/2 ~2h at 37°C. Consequently,
cisplatin must be administered in a saline solution maintaining the
chemical neutrality essential for a rapid penetration of cisplatin
into the cells through passive diffusion process. The Pt-Cl bond is
stable only when the chloride concentration is high (>100 mM) as
in the blood. However, different research works have been carried
out with different results [21]. Due to its side effects, however,
cisplatin and its derivatives have drawbacks, which have led sci-
entists to attempt different methods and ingredients in order to
obtain better specificity to target the tumor cells and not spread
to other healthy cells. Recently, a new discovery has been pub-
lished, by engaging nanomedicine, which has become a very useful
method in these years. Gold nanoparticles, for instance, were tried
in order to enhance cytotoxic activity in bile acid cisplatin
derivatives [22]. Cisplatin units have also been attached to bile
acids in oder to make them more biocompatible and target them
better to colorectal cancers [23,24].
1.2 Platinum-based anticancer drugs
Platinum-based anticancer drugs play an important role in treating
various malignant tumors. They are the backbone of drugs that are
clinically used for the treatment of different solid tu- mors: for
instance, genitourinary, colorectal, and non-small cell lung
cancers. Cisplatin, the pri- mary anticancer drug, has been widely
used for more than thirty years in standard chemotherapy
procedures, either as a single therapeutic technique or in
combination with other cytotoxic agents or radiotherapy [25]. It
has shown some spectacular successes. Nonetheless, platinum-based
an- ticancer chemotherapy is associated with serious side effects
because of poor specificity [26]. Especially for cisplatin,
systemic toxicities like nephrotoxicity, neurotoxicity,
ototoxicity, and emetogenesis impose severe disorders or injuries
on patients while the treatment is taking place, which restrict its
efficacy greatly [27]. Additionally, the efficacy of cisplatin is
often limited by the intrinsic and acquired resistance possessed by
various cancers [28]. Various mechanisms have been proposed in
order to elucidate and explain the reason behind cellular
resistance to cisplatin and its analogues in preclinical models
[29].
!4
Four representatives have been introduced, and they are:
Decreased drug accumulation or increased drug efflux. Increased
detoxification of the drug by sulfur-containing molecules within
the cells. Enhanced repair and increased tolerance to DNA damage.
Changes in molecular pathways involved in the regulation of cell
survival or cell death.
The disadvantages of cisplatin have given momentum for the
improvement of platinum-based anticancer drugs. For the last four
decades, thousands of platinum complexes have been pre- pared,
designed and developed in the hope of finding new drugs with a more
tolerable toxicolog- ical profile and higher efficacy. These
efforts have brought five different drugs into clinical use, and
they are carboplatin, oxaliplatin, nedaplatin, lobaplatin, and
heptaplatin. Each of these newly designed drugs show some
advantages over cisplatin. For example, nedaplatin shows less
nephrotoxicity and neurotoxicity than cisplatin and carboplatin.
Oxaliplatin, on the other hand, reveals less toxicity and little,
or no cross resistance, to cisplatin or carboplatin[30].
In order to explain the idea of how to further advance the field,
the primary concern in the de- velopment of platinum anticancer
agents is the drug resistance as well as systemic toxicity. This
main goal is to prepare and develop anticancer drugs that can go
directly to a cancerous cell and destroy it without harming normal
cells. However, this goal is basically elusive for such a com-
plicated disease as cancer. Nonetheless, it is possible to
contemplate the ideal scenario by devel- oping platinum-based
prodrugs that can be protected and safe in the administered form
but are cytotoxic to cancer cells after being activated under
certain conditions.
Obviously, the understanding of this ideal is driven by the tumor
selectivity of platinum com- plexes. Generally, there are at least
three advantages platinum complexes should have in the de- sign of
new anticancer drugs [31]: Constructing complexes that display
different DNA-binding modes; Exploiting prodrugs that can be
activated only in the tumor tissues; Improving drug accumulation at
the tumor site by means of an accurate targeting and delivery
strategy.
The first advantage incorporates polynuclear platinum complexes,
trans-platinum complexes, and monofunctional platinum complexes
[32]. The second one includes complexes that employ the unique
characters of solid tumors, such as acidic pH, and hypoxic or
reducing conditions. For instance, inert platinum(IV) complexes can
be reduced to cytotoxic platinum(II) complexes after being
administered with the loss of the two axial ligands under hypoxic
conditions in the tumor tissue, and thus, act as prodrugs [33].
This third category is ameliorating the selective accumula- tion of
platinum drugs in healthy tissues through targeting and delivery
techniques [13].
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Figure 2. Approved platinum-based anticancer drugs.
1.2.1. Platinum complexes and nitrogen-donor ligands
The functionality of platinum-based anticancer drugs is quite
similar to alkylating agents as they both go directly to and damage
DNA in order to prevent cancer cell from growing and re- producing.
However, these agents work in all phases of the cycle, which means
that they are not phase-specific. Yet, platinum-based anticancer
drugs are less likely than the alkylating agents to cause leukemia
later on [34]. Plainly, all of the clinically established
platinum-based anticancer drugs are endowed with nitrogen-donor
ligands that are strongly bound to the metal center. Gen- erally,
these ligands are not substituted (released) as the platinum
compound exerts its anticancer effect. Nevertheless, the nature of
the N-donor ligands dramatically influences the anticancer
properties of platinum complexes and leads to activity against
different types of cancers [35].
!6
1.2.2. History of platinum-based drugs
Platinum had been thought to have no biological activity until
Barnett Rosenberg and col- leagues, in Michigan, applied electric
current E. Coli using platinum electrodes. The bacterial cells
stopped dividing, although they kept growing to up to 300 times
their normal length (“fila- mentation”). Surprisingly, the
researchers discovered that the electric current or voltage was not
responsible for the bacterial growth. Instead, the electric current
had led to the formation of a new chemical species, and the main
new compound so produced caused the filamentation. The compound was
determined to be cis-(NH3)2 PtCl2, which turns out to be Peyrone’s
salt, discov- ered in 1845 by Michele Peyrone [36] , and this, not
the electrical field was controlling cell divi- sion. This
experiment was called “accidental discovery that led eventually to
cisplatin” by Dr. Barnett Rosenberg in Michigan.
For a long time, Dr. Rosenberg and his colleagues did not know what
they had discovered. It was thought that they might have found a
way to control cell growth with electrical currents. Two years were
spent in order to discover the reason why the electrical field
appeared to have such a profound effect. Finally, it was realized
that the cell division was being blocked not by the electric field,
but by a platinum compound released from the electrodes. Once they
recognized the compound that controlled cell division so
dramatically it was renamed cisplatin [37].
1.2.3. Mechanism of action
Cisplatin is believed to apply its anticancer features by
crosslinking and intercalating with DNA, causing cell death
“apoptosis” [38]. After introduction into the bloodstream of a
patient, cisplatin faces a high concentration of chloride in the
blood plasma, which is around 100 mM, and the high concentration
does not allow the replacement of its chloride ligands by water
mole- cules, i.e. the process of aquation is prevented.
Nonetheless, cisplatin is vulnerable to attack by proteins found in
blood plasma, in particular those that have thiol groups, such as
human serum (albumin) and the amino acid (cysteine). As a matter of
fact, studies have shown that one day after cisplatin
administration, more than 50% of the platinum in blood plasma is
protein bound [39]. This protein is able to deactivate the drug
[40] and some of the severe side effects of cis- platin treatment
[39]. However, this drug is formed together with the trans
formation which is not very cytotoxic, but is toxic and should be
removed before treatment. The concentration of the chloride
decreases inside cells, which is between 2 to 30 mM and there
replacement can take a place [41].
!7
Figure 3. Mechanism of action of cisplatin “The Discovery and
Development of Cisplatin” (R. A. Alderden, M. D. Hall, and T. W.
Hambley. J. Chem. Ed. 2006 83(5), 728-734) [42].
!8
1.3. Pt(IV)-based complexes
Nowadays, the Pt(IV) compounds have been investigated for possible
anti-tumor activity in order to obtain better understanding of
whether these platinum(IV)-based complexes can be drugs or just act
as prodrugs. If the latter, it would mean that they are reduced to
Pt(II) before reaching their DNA target, which is the common belief
[43]. A prodrug is defined as a compound that gets converted within
the body to the active form. It is usually used when the normal
active drug is either too toxic when directly administrated, or is
difficult to absorb, or has the possibility of breaking down before
it reaches the target. Pt(IV) is kinetically more inert than
Pt(II), which means Pt(IV) drugs are more stable to acidic media,
so that they may better survive the condi- tions present in the
stomach, and thus can be administered orally [44]. Pt(IV) drugs are
of partic- ular interest since they may be toxic to tumors which
are normally resistant to cisplatin.
Different platinum(IV) complexes have been under clinical trials,
but none has been approved by FDA for clinical use in the United
States. These drugs are iproplatin, tetraplatin, and
satraplatin.
Iproplatin Satraplatin Tetraplatin
Figure 4. Pt(IV)-based complexes that are going under clinical
trail.
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1.3.1 Structure activity
One of the additional feature of platinum(IV) complexes is the
six-coordinate octahedral coor- dination geometry. Having two
additional ligands allows for further tuning of the
properties.
Additionally, these complexes are basically more inert due to being
d
6
octahedral metal ions. Therefore, the deactivation of the drugs
that can occur when they interact with thiol is prevented by using
platinum(IV)-based anticancer drugs [45]. As platinum(IV)-based
complexes are inert, the reduction to Pt(II) usually occurs before
binding to the target, DNA [46]. Reduction of Pt(IV) happens with
loss of two ligand, leading to the square planar geometry
characteristic of Pt(II) complexes. It is believed that the
(monodentate) ligands that are located trans to each other will be
lost in the reduction step. Once the loss of two ligands occurs,
the mechanism of action of Pt(IV) prodrug will be fairly similar to
cisplatin, where it binds to the plasma protein and then the loss
of chloride will occur after substituting it with water molecule,
which is highly reactive towards nucleus, then the formation of
Pt-DNA will take a place in order to prevent the cell from dividing
and growing [47].
1.3.2 Proposed mechanism of action
After detecting Pt-DNA adducts of platinum(IV)-based anticancer
drugs, they were found to have identical bonding linkages to those
of Pt(II) complexes, and that led to a belief that a simi- lar
mechanism of action could apply to unreduced platinum(IV) complexes
[48].
1.4. Attaching metal center to π-bond of organic compound
The Dewar–Chatt–Duncanson model is a type of organometallic
chemistry, which describes the category of chemical attachment
between an alkene and a metal, π complex, in some organometallic
complexes. This feature has been named after Michael J. S. Dewar,
Joseph Chatt and L. A. Duncanson [49].
!10
The action takes a place when pi-acid alkene donates electron
density to the platinum d-orbital from a π symmetry bonding orbital
between the carbon atoms. Then, platinum donates electrons back
from another filled d-orbital into the vacant π antibonding
orbital. These two effects con- tribute to decrease the
carbon-carbon bond order, resulting in an elongated C-C distance
and a reduction of the vibrational frequency.
One of the well-known examples is Zeise's salt K[PtCl3(C2H4)].H2O,
which is believed to be the first organometallic [50], the C-C bond
length has increased to 1375 picometers from 1337 pm for ethylene
[51]. This cooperation motivates the carbon atoms to rehybridize
from sp2 to sp3, which is determined by the bending of the hydrogen
atoms on the ethylene back away from the metal [52].
The application of a cytotoxic COX inhibitor opens a new option for
the therapy of tumors for which it is known that an overexpression
of COX results in pathological variations. During the last years it
was demonstrated that various mammary carcinoma show increased
expression of COX-2 and that inhibitors of this enzyme can reduce
tumor growth and tumor progression. An increased COX-2 expression
in gynecologic tumors is further accompanied by a bad prognosis for
patients with mammary carcinoma as well as prostate carcinoma
[53].
1.5. Objectives of the study
Due to the severe systemic toxicity and side effects, alternative
platinum-based anticancer drugs are needed in order to obtain a
drug that has lower or no side effects. For the last four decades,
thousands of platinum-based anticancer drugs have been synthesized
for hope in finding a new drug that can be administrated with lower
dose and higher efficacy. Five new platinum- based anticancer drugs
have been synthesized and categorized under three different types,
and they are:
Chelate agents or denticity. It provides the ability to have
cis-configuration complexes which is the desired configuration for
platinum-based anticancer drugs. Pt(IV)-based complexes. A highly
active field with motivating results such as inertness before
reaching to target cells. Platinum-π backbonding complexes. A new
field with a unique property where platinum metal is attached to
the π bond of organic compounds.
!11
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50. W. C. Zeise, . "Von der Wirkung zwischen Platinchlorid und
Alkohol, und von den dabei entstehenden neuen Substanzen". Annalen
der Physik und Chemie. 1831 97 (4), 497- 541.
!15
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Bau. Neutron diffraction study of the structure of Zeise’s salt,
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!16
2.1. Introduction
One of the objectives is to synthesize platinum-based anticancer
drugs with fewer reaction steps and higher yield. As this study has
three different categories, it was necessary to have vari- ous
procedures to follow. The synthesis of the first category, chelate
agents, is done by having starting materials together in water. The
platinum center will react with the organic compound, and the
solvent to work as leaving group. Bidentate ligands have two donor
atoms, and that al- lows them to bind to a central metal atom.
Common examples of bidentate ligands are ethylene- diamine, which
can be used as a non-leaving group, and the oxalate ion, which can
be used as anionic leaving ligands. It bonds as nitrogen or oxygen
atoms on the adjacent edges of a planar Pt(II), each donor have two
free electrons that can be used to bond to a central metal atom or
ion. However, none of the approved drugs has organic bidentate
ligands and mono dentate anionic ligand, which is worth trying, as
it can have similar mechanism of action to the one of cisplatin. If
the leaving group is chloride such as DPAPlatin, its loss is
important before binding to target DNA. Another option to consider
is having water molecule as leaving group instead of chloride, such
as the leaving group of PhenPlatin. In this case, it is believed
that the complex is very reac- tive and can interact with target
DNA without any additional step. A second possibility can be
applied to PhenPlatin, which is the loss of the second platinum,
and that will lead to different drugs which can be a benefit as two
different drugs can be administrated at the same time.
!17
!18
Pt
NH2H2N
+2
-2H2O
Pt
NH2H2N
Figure 6. A possible breakout that can lead to two different drugs
of PhenPlatin.
!19
N
N
+
The second category “Pt(IV)-based complexes” differs from normal
platinum-based anti- cancer drugs as it has two additional ligands
that essentially keep the drugs inactive until they reach target
DNA. One of the additional feature of platinum(IV) complexes is the
six-coordinate octahedral coordination geometry. They have two
additional ligands which allows for further
tuning of the properties. Additionally, these complexes are
basically more inert due to being d 6
octahedral metal ions. Therefore, the deactivation of the original
platinum(II) drugs that can oc- cur when they interact with thiol
is prevented by using platinum(IV)-based anticancer drugs [1]. As
platinum(IV)-based complexes are inert, the reduction to Pt(II)
usually occurs before binding to the target, DNA [2]. Reduction of
Pt(IV) happens with loss of two ligand, leading to the square
planar geometry characteristic of Pt(II) complexes. It is believed
that the (monodentate) ligands that are located trans to each other
will be lost in the reduction step. Once the loss of two ligands
occurs, the mechanism of action of Pt(IV) prodrug will be fairly
similar to cisplatin, where it binds to the plasma protein and then
the loss of chloride will occur after substituting it with water
molecule, which is highly reactive towards nucleus, then the
formation of Pt-DNA will take a place in order to prevent the cell
from dividing and growing [3].
Figure 7. The octahedral geometry of Pt(IV)-based complexes.
!20
Pt
!21
Pt
A A
The third category “ π-bond binding” can be a new and interesting
field. The Dewar–Chatt– Duncanson model is a type of organometallic
chemistry, which describes the category of chemi- cal attachment
between an alkene and a metal, π complex, in some organometallic
complexes. This feature has been named after Michael J. S. Dewar,
Joseph Chatt and L. A. Duncanson [4].
The action takes a place when pi-acid alkene donates electron
density to the platinum d-orbital from a π symmetry bonding orbital
between the carbon atoms. Then, platinum donates electrons back
from another filled d-orbital into the vacant π antibonding
orbital. These two effects con- tribute to decrease the
carbon-carbon bond order, resulting in an elongated C-C distance
and a reduction of the vibrational frequency.
One of the well-known examples is Zeise's salt K[PtCl3(C2H4)].H2O,
which is believed to be the first organometallic [5], and its C-C
bond length increases to 1375 picometers on bonding to the metal
[6]. This action encourages the carbon atoms to have
rehybridization to sp3, which oc- curs by the bending back the
hydrogen atoms to ethylene from the metal [7]. The mechanism of
action is quite similar to the mechanism of action of chelate
agents ( figure 5).
Figure 9. Zeies’s salt.
!22
2.2. Experimental and characterization
2.2.1: Synthesis of DPAPlatin
A suspension of di-picolyamine (0.2 mmol) in water (5 mL) was
titrated with 0.1 M HCl with stirring until all the solid had
dissolved, followed by the addition of a solution of K2PtCl4 (0.18
mmol) in water (3 mL). The precipitate of Pt-complex is formed
after the above mixture has been refluxed at 70 C for 2 h. The
precipitate is collected and washed with 0.1 M HCl, water and
ethanol and then is dried at 50 C under vacuum for 5 h.
Figure 10. The mechanism of the synthesized drug “DPAPlatin”.
!23
N
N H
73% yield
2.2.2. Synthesis of PhenPlatin 1,10-phenanthrolin-5-amine (0.2
mmol) in water (5 ml) with (2 ml) of MeOH and solution was stirred
until solid was dissolved, followed by the addition of a solution
of K2PtCl4 (0.18 mmol) in water (2 ml). The precipitate of
Pt-complex is formed after the above mixture has been refluxed at
100 C for 4 h. The precipitate is collected and washed with 0.1 M
HCl, water and ethanol and then is dried at 50 C under rotary
evapo- ration for 8 hours.
Figure 11. The mechanism of the synthesized drug
“PhenPlatin”.
!24
NN
NH2
N
N
2.2.3 Synthesis of TriPicolyAminePlatin
125 mg of potassium tetrachloroplatinate (K2PtCl4) was added 200 µl
of water via a micro-syringe. The solution was heated with stirring
in an oil bath to 70 ºC. To this a solution of 300 mg of KI in 500
µl of warm water was added. The mixture was heated to 80 ºC with
continuous stirring. As soon as the temperature reached 80 ºC, the
mixture was cooled down to room temperature. The solution was
filtered using a Hirsch funnel to remove any solid impurities.
Using a syringe, 0.4 mmol of the organic compound was added with
HCl and water, after 45 min of stirring, another 0.4 mol of organic
compound is added and stirred for another 45 min. An oily complex
was obtained. The beaker was allwed to stand for an additional 20
min at room temperature [8]
Figure 12. The mechanism of the synthesis of the synthesized drug
“TriPicolyAmine- Platin”.
!25
Pt
N
H2N
2.2.4. Synthesis of DiPhenPlatin
125 mg of potassium tetrachloroplatinate (K2PtCl4) was added 200 µl
of water via a micro-syringe. The solution was heated with stirring
in an oil bath to 70 ºC. To this a solution of 300 mg of KI in 500
µl of warm water was added. The mixture was heated to 80 ºC with
continuous stirring. As soon as the temperature reached 80 ºC, the
mixture was cooled down to room temperature. The solution was
filtered using a Hirsch funnel to remove any solid impurities.
Using a syringe, 0.4 mmol of the organic compound was added. As
soon as the compound was added, fine red crystals of the complex
precipitat- ed. The beaker was allowed to stand for an additional
20 min at room temperature. The product was washed with 500 µl
ice-cold ethanol, followed by 1 ml ether [8].
Figure 13. The mechanism of the synthesized drug
“DiPhenPlatin”.
!26
NN
NH2
2.2.5. Synthesis of DCCPlatin
The hydrate is commonly prepared from K2[PtCl4] and
N,N’-dicyclohexylcarbodiimide in the presence of a catalytic amount
of SnCl2. The water of hydration can be removed in vacuo.
Figure 14. The mechanism of the synthesized drug “DCCPlatin”.
!27
Cl Cl
For the spectra of mass spectrometry, the molecular ion and the
fragmentation were calculates as shown. And for NMR, the peaks were
calculated from ChemDraw and fitted to the experi- mental
spectra.
However, since the complexes are possible anticancer agents, they
are currently being tested in Germany by Biozentrum of
Martin-Luther-Universität Halle-Wittenberg by Dr Reinhard
Paschke.
!41
2.4. References
1. J. J. Wilson and S. J. Lippard. Synthetic Methods for the
Preparation of Platinum Anticancer Complexes. Chem. Rev. 2014, 114,
4470−4495.
2. M. D. Hall, T. W. Hambley, Platinum(IV) antitumour compounds:
their bioinorganic chem- istry. Coord. Chem. Rev.
2002;232:49–67.
3. S. J. Lippard. New chemistry of an old molecule:
cis-[Pt(NH3)2Cl2]. Science, 1982, 218, 1075.
4. J. Chatt and L. A. Duncanson. Olefin co-ordination compounds.
Part III. Infra-red spectra and structure: attempted preparation of
acetylene complexes. J. Chem. Soc., 1953, 2939-2347.
5. W. C. Zeise, . "Von der Wirkung zwischen Platinchlorid und
Alkohol, und von den dabei entstehenden neuen Substanzen". Annalen
der Physik und Chemie. 1831 97 (4), 497-541.
6. R. A. Love , T. F. Koetzl, G. J. B. Williams, L. C. Andrews, R.
Bau. Neutron diffraction study of the structure of Zeise’s salt,
Inorg Chem., 1975, 14, 2653-2657.
7. G. L. Miessler, D. A. Tarr. Inorganic Chemistry. 2014 Upper
Saddle River, New Jersey: Pear- son Education, Inc. Pearson
Prentice Hall.
8. R. A. Alderden, M. D. Hall, T. W. Hambley. The Discovery and
Development of Cisplatin. J. Chem. Educ. 2006, 83, 728-733.
!42
3.1. Summary
The evolution of platinum-based anticancer drugs has long been
concentrated on the synthesis and assessment of complexes that can
attack cancer cells without harming other normal cells. These
efforts have brought five platinum-based complexes to clinical use,
which are widely em- ployed anticancer drugs. The generality of
deep-rooted and acquired resistance to platinum treatment, however,
requires the development of new complexes that operate through
various mechanisms. Despite the fact that it was initially believed
to be unproductive, thousands of po- tential platinum-based
anticancer drugs have been developed and synthesized. Additionally,
dif- ferent strategies were expounded and have shown promising
results and can be used in the future work and studies [1].
Regardless of the clinical success that has been realized by
cisplatin, car- boplatin, oxaliplatin and the other approved
platinum-based drugs, the therapy with these com- pounds still
inflicts a number of serious side-effects and disorders [2]. Among
those impacts on patient quality of life are nephrotoxicity,
fatigue, emesis, alopecia, ototoxicity, peripheral neu- ropathy,
and myelosupression [3]. In many treatment arrangements, one or
more of these side- effects will often be dose-limiting. Another
major limitation of recent platinum-based drugs is that some
categories of cancer are naturally resistant to treatment and
others develop resistance with time [4]. In an attempt to avoid the
mechanisms that give rise to such inherent or acquired resistance
and to decrease other side-effects, different platinum-based
anticancer drugs have been synthesized in order to form different
chemical properties. The theorem is that a variation in structure
will result in an adjusted mechanism of action and, consequently, a
different kind anti- cancer activity.
The application of any anticancer agent in the treatment of human
patients is restricted by its general level of toxicity. Various
platinum-based anticancer drugs have been synthesized in the hope
of increase specificity as well as reduce side effect. This battle
has introduced 5 different platinum-based anticancer drugs, and
another 10 drugs are going under clinical trial.
However, considering that the majority of these drugs function
through a similar non-specific mechanism of action, some
shortcomings of cisplatin are therefore retained, albeit to a
lesser ex- tent. Thus, simple modification of the ligands seems
unlikely to bring about a quality leap from
!43
an in discriminative drug to a ‘‘magic bullet’’. Optimally, future
platinum drugs should attack exclusively cancerous cells without
affecting normal ones, and enter the former more readily than the
latter.
Five different platinum-based anticancer drugs have been
synthesized in the hope of finding drugs with higher efficacy and
less or no side effect. These platinum complexes have various
leaving groups that differ from each other, such as methoxy,
chloride, and water. Another option was considered, which was
having a platinum-based complex that can interact or intercalate
with target DNA without the need of leaving groups, and that was
done by the synthesis of DiPhen- Plaitn, as it is believed that
1,10-phenanthroline can intercalate with DNA without the necessity
of leaving groups.
Having various chemical properties in the synthesized
platinum-based anticancer drugs in or- der to obtain a better
understanding about the diversity of each drug and how it affects
cancer cells and in the hope of categorizing these drugs into
aspects in order to facilitate their studies, It was attempted to
synthesize different compounds with different ligand properties,
seeking to un- derstand the differences between them all, and which
one is more favorable.
I. The first category to synthesize is the chelate amine ligands;
the main advantage of this form is the cis configuration, which is
the favorable form for platinum-based anticancer drugs. Cisplatin,
for example, is highly cytotoxic whereas transplatin is not
cytotoxic. Two different platinum-based complexes have been
synthesized under this category, and they are Di(2-pi-
coly)aminchloro platinum, which has one chloride as anionic ligand,
and PhenPlatin, which has four different anionic ligands, and that
might enhance the opportunity to attach to the tar- get DNA.
Another unique feature that PhenPlatin can have is the ability to
intercalate with DNA without the need of having leaving group [5],
and by having four additional anionic lig- ands, there can be a
high probability of obtaining a highly reactive drug. Plus,
PhenPlatin complex has two platinum centers that can work as two
different drugs when they are sepa- rated. Therefore, PhenPlatin
can be a motivating drug toward cancer cells.
By having at least one leaving group in order to give the drugs the
possibility to interact with the targeted DNA it is possible to
obtain a drug that can be effective toward cancer cells. The
chelate agent category has been used in the most of the approved
platinum-based anticancer drugs, which drives us to investigate
more by synthesizing more platinum-based complexes un- der the same
category.
!44
Figure 15. The synthesized platinum-based anticancer drugs under
“chelate agents” category.
!45
10890) [5].
!46
II. The second category of the synthesized drugs is Pt(IV)-based
anticancer drugs, the octahedral complexes that have been studied
lately. Three Pt(IV) complexes are currently undergoing clinical
use, and that gives a potential hope for synthesizing more drugs
that can be highly reactive towards cancer cells. Two different
platinum-based complexes have been synthesized under the category
of Pt(IV). One of these is TripicolyaminePlatin, which after the
reduction of its platinum (IV) to (II), will end up with one
chloride as mono dentate anionic ligand, and can react strongly
toward target DNA and attach to the guanine in order to block the
repro- duction of the target DNA. The second of these
platinum(IV)-based drugs is DiPhenPlatin. This second drug has two
leaving group and their loss will occur after the reduction of
Pt(IV) to Pt(II) and then the drug can intercalate with the target
DNA. The reason behind the synthe- sis of the second drug is to
obtain a drug that can be inert - “stable and not reactive” - in
the normal Pt(IV) phase, and once the drug reaches the target cell,
it would lose the leaving group to leave the drug with no anionic
ligand. As mentioned above, 1,10-phenenanthroline and its
derivatives have the ability to intercalate with DNAs [5]. Thus,
DiPhenPlatin can be a promising drug that should have the ability
to be stable and not reactive before reaching the target DNA, and
that means the body will not be effected by the drug before the
reduction occurs, and once the loss of the leaving group happens,
and the drug will be reactive toward the target DNA, which is
proposed to be those of the cancer cells. Another special feature
that DiPhenPlatin has is the ease of losing the leaving groups
which are water and methanol as both of them work as very good
leaving groups. By losing water molecule the body will not be
affected whatsoever as this amount of water is not bad to be added
to the body. However, the loss of methanol is another story, as
this is toxic to the human body, which would restrict the efficacy
if it were necessary to administer it in high dosage. Nevertheless,
one of the ob- jectives is to synthesize drugs that can be
administrated in low dosage; therefore the possibili- ty to be
effected by methanol that is attached to DiPhenPlatin is fairly
lower than the amount that will lead to danger to human body.
!47
!48
III. The third category is by having metal center attached to π
bond of organic compounds, which is a new field that is believed to
open new options for platinum-based complexes as it pro- vides a
unique property. By rehybridizing the nitrogen and the carbon of
the complex, new properties can be provided. The first
organometallic to be ever known is Zeise’s salt which was tested
for the ability to be reactive toward cancer cells. Surprisingly,
Zeise’s salt showed the capability to inhibit cyclooxygenase enzyme
“COX enzyme”, and this inhibition can pro- vide relief from the
symptoms of inflammation and pain. Therefore, an important
potential for a new application of platinum-based drugs is
cyclooxygenase inhibitors. COX-2 inhibitors are pain reducers which
cause less gastrointestinal side effects and bleeding than aspirin,
2- (acetoxy)benzoic acid, and other NSAIDS (nonsteroidal
anti-inflammatory drugs) [6]. An as- pirin analog has been attached
to Zeise’s salt and its derivatives in order to obtain a medical
vision whether Zeise’s salt and its derivatives can be effective or
not, and it gave promising results. It is believed that the
coordination of the Zeise’s salt is the effective part of the salt
[7]. In this thesis, a platinum-based drug was synthesized that has
similar coordination, where the platinum metal center is attached
to the organic compounds by the π bonds instead of the actual
atoms. By having the metal center attached to π-bond of the ethene,
the C-C bond length has increased to 1375 picometers from 1337 pm
for ethylene [8]. This coopera- tion motivates the carbon atoms to
rehybridize from sp2 to sp3, which is determined by the bending of
the hydrogen atoms on the ethylene back away from the metal
[9].
The application of a cytotoxic COX inhibitor opens a new option for
the therapy of tumors for which it is known that an overexpression
of COX results in pathological variations. During the last years it
was demonstrated that various mammary carcinoma show increased
expression of COX-2 and that inhibitors of this enzyme can reduce
tumor growth and tumor progression. An increased COX-2 expression
in gynecologic tumors is further accompanied by a bad prognosis for
patients with mammary carcinoma as well asprostate carcinoma [10].
In order to have a fur- ther understanding, one drug has been
synthesized under this category, and it is DCCPlatin. By having the
platinum attached to two π-bonds of N,N-dicyclohexylcarbodiimide, a
new and unique feature can occur, which can open a new field of new
platinum-based complexes that share similar properties. However,
the new feature of DCCPlatin that no drug has, is having ni- trogen
that is attached to each double-bond, which can provide a special
feature.
!49
Figure 18. Design and reactivity of potassium
[2-(prop-2-enol)-2-ace- toxybenzoat]trichloro- platinate(II)
(Pt-Propenol-ASS) {S. Meieranz, M. Stefanoupoulou, G. Rubner, K.
Bensdorf, D. Kubutat, W. S. Sheldrick and R. Gust. The Biological
Activity of Zeise’s Salt and its Derivatives.
Angew Chem Int Ed Engl. 2015, 54(9), 2834-2837.[7]}.
!50
N,N- dicyclohexylcarbodiamindichloro platinum (II)
Figure 19. DCCPlatin that has the platinum attached to the π-bonds
of N,N- dicyclohexylcarbo- diamindichloro.
!51
3.2. Future work
The lack of specificity of platinum-based anticancer drugs is the
main issue that needs to be addressed in order to increase the
efficacy of the drugs. Thousands of platinum complexes have been
synthesized, designed, and developed to achieve the goal where the
drugs can be used with no side effect that harms normal cells.
Personally, I have synthesized eight different platinum- based
anticancer drugs with different chemical properties. However,
further projects can be un- der consideration for future studies,
and they include:
3.2.1. Tethering carboxylic acid
Drug targeting and delivery represents an exceedingly active area
of research for platinum- based anticancer drugs that can move
directly to their biological targets [11]. Comparing with classical
chemotherapy, targeted therapy for cancers has two main benefits,
which are the eva- sion of harming normal tissues, and control of
drug resistance. In the past years, differs drug tar- geting and
delivery paths have been promoted in a pursuit to decrease the
systemic toxicity and drug resistance of platinum-based anticancer
drugs [12]. The eventual objective of these attempts is to gain
platinum drugs that are supremely selective for tumor tissues and
can be distributed at lower doses with less side effects and an
enhanced therapeutic index [13]. Carriers such as es- trogens,
carbohydrates, carbon nanotubes, and nanoparticles would be
possible candidates. As indicated in other literature (Xiaoyong
Wang and Zijian Guo. 2013) these carriers have shown very promising
results.
3.2.2. More of platinum-based (IV) anticancer drugs
Amid the figure of the prepared and biomedically screened platinum
complexes, octahedral complexes with platinum(IV) center, including
satraplatin, tetraplatin, iproplatin, and ormaplatin, have been
tested as potential anticancer agents particularly against
cisplatin resistant tumor cell lines [14]. Pt(IV) complexes with
octahedral structure have advantages over the Pt(II) complexes
because of their kinetic inertness. This controls release of Pt(II)
and and thus toxicity is less compared to Pt(II) analogs [15].
Pt(IV) drugs are considered prodrugs because they need to be
reduced intra- or extra-cellularly by biological reductants such as
glutathione, ascorbic acid, and cystein to Pt(II) complexes in
order to become reactive. Based on a literature work (Hien T. T.
Duong, Vien T. Huynh, Paul de Souza, and Martina H. Stenzel. 2010)
platinum-based (IV) anti- cancer drugs can give a very hopeful
result [16].
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3.2.3. Tethering carboxylic acid
The transformation of neutral platinum(II) drugs is necessary in
order to get a reactive bifunc- tional electrophile outcomes in the
coordinate binding of the nucleophilic bases in the DNA. However,
the existence of the very slow-leaving oxalic acid group in some
platinum complexes has led to a realization that other mechanisms
might also exist for the prodrug activation. Addi- tionally, the
presence of the carboxylic acids can greatly enhance the reactive
oxygen species, ROS, that is produced by platinum-based drug
complexes. The enhanced ROS could eventually moderate the cellular
damage, leading to the developed cytotoxicity via the apoptosis
pathway. Accordingly, it is noticed that the carborane–carboxylic
acid derivatives either monodentate car- boxylic acid, or bidentate
carboxylic acid show an obvious effect on the biological toxicities
of platinum-based drug complexes toward cancer cells, even stronger
than the carboranes, which have no enhanced effect on the
cytotoxicity. It is suggest that the negatively charged carboxylic
groups in carborane–carboxylic acids can readily lead to
self-assembled composites of the carbo- rane–carboxylic acid
derivatives on the positively charged surface of Platinum-based
drug com- plexes through electrostatic interactions [17].
An example to take, carboplatin, which was introduced as a second
generation anticancer drug during the mid-1980s [18] in response to
the severe side effects exhibited by its predecessor, cis- platin.
Since then, this drug has gained wide acceptance in the clinical
treatment of different can- cers [19], the dose- limiting factor
being myelosuppression. Carboplatin possesses a slowly aquating,
ringlike, bulky side group, i.e. the 1,1-cyclobutanedicarboxylato
group, instead of the readily leaving chloro groups in cisplatin.
Therefore, attaching carboxylic acid to the synthesized
platinum-based anticancer drugs is worth trying.
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