Western Michigan University ScholarWorks at WMU
Master's Theses Graduate College
8-2015
Synthesis of New Platinum-Based Anti-Cancer Drugs
Saud O. Albaroodi Yasser
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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
This Masters Thesis-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Master's Theses by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. SYNTHESIS OF NEW PLATINUM-BASED ANTI-CANCER DRUGS
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
ii TABLE OF CONTENTS
ACKNOWLEDGEMENTS……….…………………………………………………………….ii
LIST OF FIGURES………………….…………………………………………………………vi
LIST OF ABBREVIATION………………..………………………………………………… vii
Chapter
1. INTRODUCTION…………………………………………………………………………….1
1.1. Cancer……………………………………….………………….………………………..1
1.1.1. Cancer treatment…………………………………………………………………….2
1.1.1.1. Surgery……………………………………………………………………………2
1.1.1.2. Hormone therapy…………………………………………………………………2
1.1.1.3 Immunotherapy……………………………………………………………………2
1.1.1.4. Radiation therapy…………………………………………………………………2
1.1.1.5. Targeted therapy…………………………………………………………………..2
1.1.1.6. Chemotherapy…………………………………………………………………….3
1.1.2. Approved platinum-based drugs………………………………………………………3
1.1.3. Side effects of platinum-based drugs……………………………………………….3
1.1.4. Platinum-based complexes………………………………………………………….3
1.2. Platinum-based anticancer drugs…………………………………………………………4
1.2.1. Platinum complexes and nitrogen-donor ligands……………………………………6
1.2.2. History of platinum-based drugs…………………………………………………….7
iii Table of Contents - continued
1.2.3. Mechanism of action…………………………………………………………………7
1.3. Pt(IV)-based complexes…………………………………………………………………..9
1.3.1. Structure activity……………………………………………………………………10
1.3.2. Proposed mechanism of action……………………………………………………..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. CHARACTERIZATION OF PT-BASED ANTI-CANCER DRUGS………………………17
2.1. Introduction………………………………………………………………………….…..17
2.2. Experimental and characterization………………………………………………………23
2.2.1. Synthesis of DPAPlatin……….…………………………………………………….23
2.2.2. Synthesis of PhenPlatin….………………………………………………………….24
2.2.3. Synthesis of TriPicolyAminePlatin…………………………………………………25
2.2.4. Synthesis of DiPhenPlatin………………………………………………………….26
2.2.5. Synthesis of DCCPlatin…….………………………………………………………27
2.3. Results and fragmentation………………………………………………………………28
2.3.1. Characterization of DPAPlatin………………………………….…………………..30
2.3.2. Characterization of PhenPlatin……………………………….…………………….33
2.3.3. Characterization of TriPicolyAminePlatin…………………………………………35
2.3.4. Characterization of DiPhenPlatin………………………………………………….37 iv Table of Contents - continued
2.3.5. Characterization of DCCPlatin…………………………………………………….40
2.4. References……………………………………………………………………………….42
3. SUMMARY AND FUTURE WORK…………………………………………………………43
3.1. Summary……………………………………………………………………………….43
3.2. Future work…………………………………………………………………………….52
3.2.1. Tethering carriers to the drugs……………………………………………………..52
3.2.2. More of platinum (IV) anticancer drugs…………………………………………..52
3.2.3. Tethering carboxylic acid…………………………………………………………53
3.3. References……………………………………………………………………………..54
v LIST OF FIGURES
1. Cancer statistics in the U.S. in 2015……………………………………………………………1
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 LIST OF ABBREVIATION
COX……………………………………………………………………………….Cyclooxygenase
DNA………………………………………………………………………..Deoxyribonucleic acid
DTD…………………………………………………………………..Drug targeting and delivery
ER………………………………………………………………………………..Estrogen receptor h……………………………………………………………………………………………….Hour
HCl……………………………………………………………………………………Hydrochloric
MeOH…………………………………………………………………………………….Methanol mg……………………………………………………………………………………….Milli gram min…………………………………………………………………………………………..Minute
µl…………………………………………………………………………………………Microliter
%……………………………………………………………………………………………Percent
vii CHAPTER 1 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.