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Based HDAC-Inhibitors As Anti-Cancer Agents A Thesis entitled Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents by Shaimaa Hesham Sindi Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry ___________________________________________ L.M. VIRANGA TILLEKERATNE, D.Phil, Committee Chair ___________________________________________ JAMES T. SLAMA, Ph.D, Committee Member ___________________________________________ KATHERINE A. WALL, Ph.D., Committee Member ___________________________________________ ZAHOOR SHAH, Ph.D, Committee Member ___________________________________________ Dr. Cyndee Gruden, Dean College of Graduate Studies The University of Toledo August 2019 Copyright 2019 Shaimaa Hesham Sindi This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Guanidine- Based HDAC-Inhibitors as Anti-Cancer Agents by Shaimaa Hesham Sindi Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Masters of Science Degree in Medicinal Chemistry The University of Toledo August 2019 Abstract. It is evident that epigenetics plays an important role in gene regulation. Consequently, any disruption in epigenetic memory will manifest into gene expression and lead to long-established transformation events. Covalent modification of histone is one of the epigenetic regulation mechanisms, and includes acetylation, methylation, phosphorylation, and ubiquitylation among others. Combination of two or more of these modifications acts like a sensor for gene expression or gene repression through highly condensed or uncondensed chromatin structures. The cancer epigenome is specifically marked with global DNA methylation and histone alteration patterns. The gene regulation is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation through HATs results in expansion of chromatin, and thus increases the accessibility of transcription factors to DNA. On the other hand, the deacetylation with HDACs leads to very condensed chromatin structures and consequently, to transcription repression. Owing to their specificity for cancer cells, HDAC inhibitors have now become a powerful target in anticancer drug development. The pharmacophore iii of HDAC inhibitors consists of a zinc-binding group, a linker and a capping group. These drugs exert their effect on cancer cells by arresting them in G1 or G2-M phases of the cell cycle, or by induction of differentiation and apoptosis. They can also inhibit angiogenesis and metastasis and regulate the host immune response. Generally, HDACs can be classified into four different classes (class I, II, III, and IV). It is well established that most HDAC inhibitors in clinical use lack specificity. It is believed that variations in the nature of the capping group can lead to variations in HDAC inhibitory activity and isoform selectivity. Our group has successfully developed a new class of HDAC inhibitors incorporating an imidazole ketone moiety as the capping group. Cytotoxicity studies of these molecules have shown promising activity. Efforts are underway in our laboratory to modulate the activity and selectivity of these compounds by changing the capping group. Guanidines have been reported to possess a wide range of biological activity. The biochemical and biophysical properties of guanidine are partly attributed to their specific hydrogen bonding, Y aromaticity, and stacking properties. A molecule with such properties is able to bind to carboxylates, phosphates and metals. In this study, several HDAC inhibitors with imidazole ketone metal-binding group and guanidine moieties as the capping group were designed for synthesis and methods for making versatile cyclic guanidine molecules to be used in the synthesis of HDAC inhibitors were developed. In addition, two HDAC inhibitors incorporating guanidine moieties were synthesized. One of the analogues showed potent cytotoxic properties in the NCI 60 cell line assay with a mean growth inhibition of 64.5% and GI50 values in the low micro molar range against some cell lines. The cytotoxic activity of the compound was confirmed in studies iv performed in the laboratory of Dr. William Taylor of the biological Sciences Department. The other compound did not show activity in studies carried out in Dr. Taylor’s lab and is yet to be tested at NCI for its cytotoxic activity. The incorporation of other guanidine moieties in to target molecules proved problematic, probably due to poor nucleophilicity of their amine groups. However, synthesis of these target molecules using different reaction conditions and changing synthetic design is currently in progress. v In memory of Hesham Bakour Sindi & Asmaa Yehya Aladdin With all love to Eman Sindi, Hani Sindi, Bakour Sindi, Elaf Sindi, Mohammed Abdulghani Sindi, and Ghena Mohammed Sindi and Endri Karaj vi Acknowledgements I would like to express my deepest gratitude for my supervisor, Dr. Tillekeratne, without whom my scientific career would have never taken off. Dr. Tillekeratne not only took a chance on me when no one else would, but he honed my skills in the lab and helped me identify my true passion. He gave me his time, guided me and helped me obtain a well- rounded training during the course of these two years. I am fortunate for receiving my training from such a revered scientist so early in my career. I would like to thank my committee members for the support and guidance of Dr. Slama, Dr. Shah, and Dr. Wall. I am so honored to work with person whose life is all about chemistry, his passion about chemistry push me to explore the same feeling about it. To be very grateful, this work is collaboration between Endri Karaj, and me, and it would not have been done without his effort. I would like to thank my friend who is family to me Endri Karaj. I would like to thank my colleagues, for the lab guidance, and support. I would never find better chance than educational platform to thank my sister Eman Sindi appropriately. After my parents passed away, she was emotionally and financially support for us, despite that she is on the same age of me, she gave up many things in her life for us, she is equal to life for me, and without her, I will not be writing these words. I would like to thank Hani Sindi, Bakour Sindi, Elaf Sindi, and Mohammed Abdulghani Sindi, Ghena Mohammed Sindi, my family for all support and love. vii Table of Contents Abstract ........................................................................................................................................... iii Acknowledgements........................................................................................................................ vii Table of Contents .......................................................................................................................... viii List of Tables ................................................................................................................................... ix List of Figures ................................................................................................................................... x List of Schemes ............................................................................................................................... xi List of Spectra .................................................................................................................................xiii List of Abbreviations and Definitions ............................................................................................. xv Introduction. ................................................................................................................................... 1 Epigenetics in cancer ................................................................................................................... 1 Chromatin structure and histone post- translational modifications ........................................... 2 Impact of histone acetylation and deacetylation on cancer ....................................................... 5 Isoforms of histone deacetylases ................................................................................................ 6 The molecular mechanism of HDAC inhibitors ............................................................................ 8 Direct effect on gene regulation .................................................................................................. 9 Effects of HDAC inhibitors on non-histone proteins .................................................................. 13 Guanidines in HDAC inhibitors ................................................................................................... 15 Results and Discussion ................................................................................................................. 22 Chemistry ................................................................................................................................... 24 Biological studies ....................................................................................................................... 44 Conclusion and future directions ............................................................................................... 49 Experimental and Materials ........................................................................................................... 50 Experimental
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