Synthesis of New Platinum-Based Anti-Cancer DrugsMaster's Theses Graduate College
Saud O. Albaroodi Yasser
Part of the Chemistry Commons
Recommended Citation Recommended Citation Albaroodi Yasser, Saud O., "Synthesis of New Platinum-Based Anti-Cancer Drugs" (2015). Master's Theses. 618. https://scholarworks.wmich.edu/masters_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
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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
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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
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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-
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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].
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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].
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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].
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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].
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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
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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].
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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.
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28. P. Heffeter, U. Jungwirth, M. Jakupec, C. Hartinger, M. Galanski, L. Elbling, M. Micksche, B. Keppler and W. Berger. Resistance against novel anticancer metal compounds: Differences and similarities. Drug Resist. Updates, 2008, 11, 1–16.
29. D. J. Stewart. Mechanisms of resistance to cisplatin and carboplatin. Crit. Rev. Oncol. Hematol., 2007, 63, 12–31.
30. K. Hanada, K. Asano, T. Nishimura, T. Chimata, Y. Matsuo, M. Tsuchiya and H. Ogata, J. Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppres- sion among the platinum anti tumor derivates cisplatin, carboplatin and nedaplatin in rats. Pharm. Pharmacol., 2008, 60, 317–322.
31. B. Stordal, N. Pavlakis and R. Davey. Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review. Cancer Treat. Rev., 2007, 33, 347–357.
32. M. A. Jakupec, M. Galanski, V. B. Arion, C. G. Hartinger and B. K. Keppler. Antitumour metal compounds: more than theme and variations. Dalton Trans. 2008, 183–194.
33. X. Y. Wang. Fresh platinum complexes with promising antitumor activity. Anti-Cancer Agents Med. Chem., 2010, 10, 396–411.
34. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/ chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/ chemotherapy-principles-types-of-chemo-drugs.
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http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs
35. A. Galanski, V.B. Arion, M.A. Jakupec, B.K. Keppler. Recent developments in the field of tumor-inhibiting metal complexes. Curr. Pharm. Design, 2003, 9, 2078- 2089
36. M. Peyrone, “Ueber die Einwirkung des Ammoniaks auf Platinchorur” [On the influence of Ammonia on Platinum Chloride. Ann. Chem. Pharm. 1844, 51, 1
37. B. Rosenburg. Inhibition of Cell Division in E coli by Electrolysis Products from a Platinum Electrode. Nature 1965. 205, 698 - 699
38. M. Galanski, B. K. Keppler. Carboxylation of Dihydroxoplatinum(IV) Complexes via a New Synthetic Pathway. Inorg. Chem. 1996, 35, 1709–1711.
39. R. C. DeConti, B. R. Toftness, R. C. Lange, W. A. Creasey. Clinical and Pharmacological Studies with cis-Diamminedichloroplatinum(II). Cancer Res. 1973, 33, 1310–1315.
40. F. Kratz, B. K. Keppler. In Metal Complexes in Cancer Chemotherapy;. VCH: Weinheim, Germany, 1993, pp 391–429.
41. S.E. Miller, D.A. House. The hydrolysis products of cis-diamminedichloroplatinum(II). I. The kinetics of formation and anation of the cis-diammine(aqua)chloroplatinum(II) cation in acidic aqueous solution. Inorg. Chim. Acta, 1989, 161, 131-137.
42. R. A. Alderden, M. D. Hall, and T. W. Hambley. The Discovery and Development of Cis- platin. J. Chem. Ed. 2006 83(5), 728-734
43. H. Hindman and D. P. Whittle, Oxid. Met., 1982, 18, (5/6), 245. 44. M. D. Hall, T. W. Hambley. Platinum(IV) antitumour compounds: their bioinorganic chem-
istry. Coord Chem. Rev. 2002, 232, 49-67. 45. J. J. Wilson and S. J. Lippard. Synthetic Methods for the Preparation of Platinum Anticancer
Complexes. Chem. Rev. 2014, 114, 4470−4495. 46. S. J. Lippard. New chemistry of an old molecule: cis-[Pt(NH3)2Cl2]. Science, 1982, 218,
1075- 1082. 47. B. Lippert. Impact of Cisplatin on the recent development of Pt coordination chemistry: a
case study Coord. Chem. Rev. 1999, 182, 263- 295.
48. M. D. Hall, S. Amjadi. M. Zhang, P. J. Beale, T. W. Hambley, The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines. J. Inorg. Biochem. 2004, 98, 1614– 1624
49. 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- 2947.
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.
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51. 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.
52. G. L. Miessler, D. A. Tarr. Inorganic Chemistry. 2014 Upper Saddle River, New Jersey: Pear- son Education, Inc. Pearson Prentice Hall.
53. N. Auner, U. Klingebiel, W. A. Herrmann, G. Brauer. Synthetic Methods of Organometallic and Inorganic Chemistry. Stuttgart ; New York : Georg Thieme Verlag, 1996.
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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.
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Pt
NH2H2N
+2
-2H2O
Pt
NH2H2N
Figure 6. A possible breakout that can lead to two different drugs of PhenPlatin.
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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.
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Pt
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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.
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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”.
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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”.
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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”.
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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”.
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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”.
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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.
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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.
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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
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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.
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Figure 15. The synthesized platinum-based anticancer drugs under “chelate agents” category.
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10890) [5].
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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.
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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.
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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]}.
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N,N- dicyclohexylcarbodiamindichloro platinum (II)
Figure 19. DCCPlatin that has the platinum attached to the π-bonds of N,N- dicyclohexylcarbo- diamindichloro.
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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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3.3. References
1. T. C. Johnstone, G. Y. Park, and S. J. Lippard. Understanding and Improving Platinum Anti- cancer Drugs – Phenanthriplatin. 2014. Anticancer Res. 2014 34(1), 471-6
2. D. D. Von Hoff, R. Schilsky, C. M. Reichert, R. L. Reddick, M. Rozencweig, R.C. Young, F. M. Muggia. Toxic effects of cis-dichlorodiammineplatinum(II) in man. Cancer Treat Rep. 1979, 63, 1527– 1531.
3. A. Coates, S. Abraham, S. B. Kaye, T. Sowerbutts, C. Frewin, R. M. Fox, Tattersall MH. On the receiving end – patient perception of the side-effects of cancer chemotherapy. Eur J Can- cer Clin Oncol. 1983, 19, 203–208.
4. L.P. Martin, T.C. Hamilton, R.J. Schilder. Platinum resistance: The role of DNA repair path- ways. Clin Cancer Res. 2008, 14, 1291–1295.
5. A. Robertazzi, A. V. Vargiu, A. Magistrato, P. Ruggerone, P. Carloni, P. de Hoog, and J. Reedijk. Copper-1,10-Phenanthroline Complexes Binding to DNA: Structural Predictions from Molecular Simulations. J. Phys. Chem. B 2009, 113, 10881–10890.
6. T. Kurth, C. H. Hennekens, J. E. Buring, J. M. Gaziano, Aspirin, NSAIDs, and COX- 2 inhibition in cardiovascular disease: Possible interaction and implications for treat- ment of rheumatoid. Curr Rheumatol Rep. 2004 6(5), 351-356.
7. 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
8. R. A. Love , T. F. Koetzl, G. J. B. Williams, L. C. Andrews, R. Bau. Neutron dif- fraction study of the structure of Zeise’s salt, Inorg. Chem., 1975, 14, 2653-2657.
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