Georgia State University ScholarWorks @ Georgia State University Chemistry Dissertations Department of Chemistry Fall 12-17-2014 Synthesis of Aza-Heterocyclic Monoamidines as Potential DNA Minor Groove Binders, Anti-Trypanosomals, and Boron Neutron Capture Therapy Agents Julius Green Follow this and additional works at: https://scholarworks.gsu.edu/chemistry_diss Recommended Citation Green, Julius, "Synthesis of Aza-Heterocyclic Monoamidines as Potential DNA Minor Groove Binders, Anti- Trypanosomals, and Boron Neutron Capture Therapy Agents." Dissertation, Georgia State University, 2014. https://scholarworks.gsu.edu/chemistry_diss/101 This Dissertation is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. SYNTHESIS OF AZA-HETEROCYCLIC MONOAMIDINES AS POTENTIAL DNA MINOR GROOVE BINDERS, ANTI-TRYPANOSOMALS, AND BORON NEUTRON CAPTURE THERAPY AGENTS by JULIUS GREEN I Under the Direction of David W. Boykin ABSTRACT A series of combilexin-like monoamidines has been synthesized by linking an intercala- tive unit with the DNA minor groove binder DB 818 via “Click chemistry.” DB 818 is a dicationic minor groove binder that has shown strong binding affinity to AT sequences. The aim was to synthesize novel classes of DNA minor groove binders that are combilexin-like – minor groove binder / intercalator hybrid – as potential unique DNA binding agents and therapeutics against African Sleeping Sickness. Additionally, a series of novel benzo[d]1,3,2-diazaboroles DAPI derivatives were also synthesized and investigated. These boron compounds have the po- tential to be strong DNA minor groove binders because of their lower pK a and act as potential chromophores for Boron Neutron Capture Therapy. INDEX WORDS: Combilexin, Diazaborole, DNA minor groove binder, African Sleeping Sick- ness SYNTHESIS OF AZA-HETEROCYCLIC MONOAMIDINES AS POTENTIAL DNA MINOR GROOVE BINDERS, ANTITRYPANOSOMALS, AND BORON NEUTRON CAPTURE THERAPY AGENTS by JULIUS GREEN I A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2014 Copyright by Julius Michael Albert Green I 2014 SYNTHESIS OF AZA-HETEROCYCLIC MONOAMIDINES AS POTENTIAL DNA MINOR GROOVE BINDERS, ANTITRYPANOSOMALS, AND BORON NEUTRON CAPTURE THERAPY AGENTS by JULIUS GREEN I Committee Chair: David W. Boykin Committee: Al Baumstark Kathryn B. Grant W. David Wilson Electronic Version Approved: Office of Graduate Studies College of Arts and Sciences Georgia State University December 2014 iv DEDICATION I dedicate this work to my friends and family who loved and believed in me before I loved and believed in myself, and gave me the positive support I needed at a crucial development point in my life that has finally given me the confidence to stand tall and embrace who I really am. v ACKNOWLEDGEMENTS I wish to acknowledge the support of my lab mates, particularly Arvind Kumar and Jenif- er Draper for their help. vi TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................. v LIST OF TABLES ......................................................................................................... xiii LIST OF FIGURES ....................................................................................................... xiv 1 INTRODUCTION...................................................................................................... 1 1.1 DNA ...................................................................................................................... 2 1.2 Structure .............................................................................................................. 3 1.2.1 Phosphate backbone ....................................................................................... 4 1.2.2 Sugar pucker ................................................................................................... 4 1.2.3 Base pairs ........................................................................................................ 5 1.3 Hydrogen bonding ............................................................................................... 7 1.3.1 Scales for hydrogen bond donors and acceptors ........................................... 9 1.4 Minor groove binders........................................................................................ 10 1.5 DAPI ................................................................................................................... 12 1.5.1 Benzimidazole-DAPI ..................................................................................... 12 1.5.2 DB293 and DB818 ........................................................................................ 13 1.6 Intercalators ....................................................................................................... 15 1.7 Combilexins........................................................................................................ 16 1.8 Kinetoplastidia ................................................................................................... 17 1.8.1 Protozoa ......................................................................................................... 18 vii 1.8.2 Kinetoplast DNA ........................................................................................... 18 1.8.3 Trypanosoma brucei ..................................................................................... 19 1.9 Suzuki coupling ................................................................................................. 23 1.10 1,2,3-Triazole .................................................................................................. 26 1.10.1 “Click chemistry” ........................................................................................ 26 1.11 Benzimidazole ................................................................................................ 30 1.12 Amidine........................................................................................................... 31 1.12.1 Amidine Synthesis ....................................................................................... 32 1.13 Diazaboroles ................................................................................................... 33 1.14 Boron neutron capture therapy .................................................................... 35 1.15 Microwave synthesis ...................................................................................... 36 2 EXPERIMENTAL.................................................................................................... 39 2.1 General information .......................................................................................... 39 2.2 Combilexin DB818 derivatives ......................................................................... 39 2.2.1 Suzuki coupling ............................................................................................. 39 2.2.2 Alkylations ..................................................................................................... 41 2.2.3 Azidations ...................................................................................................... 43 2.2.1 “Click chemistry” .......................................................................................... 46 2.2.2 Combilexin amidines..................................................................................... 55 2.3 DAPI boron derivatives .................................................................................... 61 viii 3 RESULTS and DISCUSSION ................................................................................. 67 3.1 DB818 combilexins ............................................................................................ 67 3.1.1 Chemistry ....................................................................................................... 67 3.1.2 DB 818 Analogues DNA Binding and T. b. r. Results ................................ 77 3.2 Potential DAPI boron derivatives .................................................................... 84 3.2.1 Properties of Diazaborole ............................................................................. 85 3.2.2 Diazaborole chemistry................................................................................... 91 4 CONCLUSIONS .................................................................................................... 104 3.3 DB818 combilexins .......................................................................................... 104 3.4 DAPI boron derivatives .................................................................................. 104 REFERENCES .............................................................................................................. 105 APPENDICES ............................................................................................................... 116 1H NMR ...................................................................................................................... 116 I ................................................................................................................................ 116 II .............................................................................................................................