This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Novel Ligands Targeting the DNA/RNA Hybrid and Telomeric Quadruplex as Potential Anticancer Agents Islam, Mohammad Kaisarul Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 10. Oct. 2021 Novel Ligands Targeting the DNA/RNA Hybrid and Telomeric Quadruplex as Potential Anticancer Agents A dissertation submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy Mohammad Kaisarul Islam Institute of Pharmaceutical Sciences School of Biomedical Sciences King’s College London Supervisors Professor David E. Thurston Dr Khondaker Miraz Rahman December 2015 1 Dedicated to my parents Late Mohammad Fakhrul Islam & Mrs Momtaz Islam 2 Plagiarism statement This thesis describes research conducted in the School of Pharmacy, UCL and King’s College London, University of London between October 2011 and April 2015 under the supervision of Professor David E. Thurston and Dr Khondaker Miraz Rahman. I declare that the research described in this thesis is unique and I have clearly mentioned the part that was conducted by our research collaborators. I also declare that all the text in this thesis has been written by me and that the parts that have already appeared in publication have been suitably recorder. Signature: _____________________________________ Date: ________________ 3 Acknowledgement Firstly, I should like to express my sincere gratitude and profound thanks to my respected supervisors, Dr Khondaker M Rahman and Professor David E. Thurston for their valued supervision and encouraging support throughout my research work. I appreciate the generous help and guidance of Dr Luengo Arratta Sandra of my group for her guidance, support and direction during the course of my chemistry laboratory work. I am very thankful to Dr Paul J M Jackson for his continuous support in carrying out the molecular modelling studies of my synthesized molecules and subsequent advice regarding SAR of the molecules. I also acknowledge Mr Meir Touitou for his support in the molecular modelling and dynamics studies. I should like to acknowledge Dr George Procopiou, Dr Nicolas Veillard and Dr Fabrizio Minicone for their valuable suggestions and guidance with the synthesis, and purification of the molecules. I should like to express my gratitude to Dr Tam Bui from Biomolecular Spectroscopy Centre, Pharmaceutical Optical & Chiroptical Spectroscopy Facility, King's College London for helping with the CD analysis of the synthesised compounds. I should also like to thank Amrit Varsha (visiting researcher) and Jeerapat Doungchawee (MSc student) for kind help in the biological evaluation of the synthesised molecules. I am highly grateful to Kazi Sharmin Nahar, Kamrun Nahar, Christopher Chamberlain, Julia Mantaj, David Corcoran, AKM Azadur Rahman, Pietro Picconi, Rashedul Islam, Jennifer Auer, Paolo Andriollo and Fransesco Cascio from my group for their generous help and encouragement. Finally, I want to acknowledge the tremendous support that I received from my family members, particularly my wife, Mrs Israt Zahan Eti, my mother, Mrs Momtaz Islam, my uncle, Dr M Khairul Hossain and my aunty, Mrs Sabera Hossain during the course of my PhD studies. 4 Table of Contents List of Figures ...................................................................................................................... 10 List of Tables ...................................................................................................................... 18 Abbreviations ...................................................................................................................... 19 Abstract ...................................................................................................................... 21 Chapter 1: Introduction ....................................................................................................... 23 1.1 Cancer and General Overview ............................................................................. 23 1.2 Hallmarks of Cancer ............................................................................................. 26 1.2.1 Sustaining proliferative signalling ....................................................................... 26 1.2.2 Evading growth suppressors ............................................................................... 27 1.2.3 Evading programmed cell death or apoptosis.................................................... 27 1.2.4 Limitless replicative potential............................................................................... 28 1.2.5 Sustained angiogenesis ........................................................................................ 28 1.2.6 Tissue invasion and metastasis ........................................................................... 28 1.3 Treatment Options for Cancer ............................................................................. 30 1.3.1 Chemotherapy ........................................................................................................ 30 1.3.1.1 DNA targeted agents ....................................................................................... 31 1.3.1.2 Antimetabolites ................................................................................................ 34 1.3.1.3 Antitubulin Agents ............................................................................................ 35 1.3.1.4 Molecularly targeted agents ............................................................................. 35 1.3.1.5 Hormonal therapy ............................................................................................ 37 1.3.2 Antibody-drug conjugates (ADC) for cancer therapy ........................................ 38 1.3.3 Radiotherapy .......................................................................................................... 38 1.3.4 Biotherapy or immunotherapy ............................................................................. 39 1.3.5 Photodynamic therapy (PDT) ............................................................................... 39 1.3.6 Surgery .................................................................................................................... 39 1.4 DNA Structure ....................................................................................................... 39 1.4.1 Double Helical DNA .............................................................................................. 42 1.4.1.1 A-DNA ........................................................................................................ 43 1.4.1.2 B-DNA ........................................................................................................ 44 1.4.1.3 Z-DNA ........................................................................................................ 44 5 1.4.2 Triplex DNA ........................................................................................................... 46 1.4.3 Quadruplex DNA .................................................................................................. 47 1.4.4 i-Motif ..................................................................................................................... 49 1.5 DNA Major and Minor Grooves ........................................................................... 50 1.6 Telomeric DNA ...................................................................................................... 51 1.6.1 Functional Assembly of Human Telomerase .................................................... 55 1.6.1.1 RNA Subunit, hTR ...................................................................................... 55 1.6.1.2 Protein Subunit, hTERT ............................................................................. 56 1.6.2 Telomeric DNA/RNA Hybrid Duplex ................................................................... 56 1.6.2.1 Structure and stability of DNA/RNA hybrid ...................................................... 59 1.6.3 Telomeric G-quadruplex Structure ..................................................................... 61 1.6.3.1 G-quadruplex structures in promoter regions ............................................ 68 1.7 Telomerase and Cancer ......................................................................................