The Use of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities
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University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Graduate School Professional Papers 2010 The seU of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities Joshua Bryant Phillips The University of Montana Let us know how access to this document benefits ouy . Follow this and additional works at: https://scholarworks.umt.edu/etd Recommended Citation Phillips, Joshua Bryant, "The sU e of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities" (2010). Graduate Student Theses, Dissertations, & Professional Papers. 1100. https://scholarworks.umt.edu/etd/1100 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES by Joshua Bryant Phillips B.S. Chemistry, Northern Arizona University, 2002 B.S. Microbiology (health pre-professional), Northern Arizona University, 2002 Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry The University of Montana June 2010 Phillips, Joshua Bryant Ph.D., June 2010 Chemistry THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES Advisor: Dr. Nigel D. Priestley Chairperson: Dr. Bruce Bowler ABSTRACT Since Alexander Fleming first noted the killing of a bacterial culture by a mold, antibiotics have revolutionized medicine, being able to treat, and often cure life-threatening illnesses and making surgical procedures possible by eliminating the possibility of opportunistic infection. However, during the past 30 years many of the infections that were once easily cured by the proper antibiotic are no longer so due to a precipitous rise in multi- drug resistant organisms. This rise in multi-drug resistant organisms poses a grave threat to the medical advances that have been made in the past century and underscores the need for new antibiotics. We have developed two promising candidates for pharmaceutical applications, compounds 72 and 71, which are derived from nonactin, a biologically active natural product. Nonactin 40, an ionophore macrotetrolide antibiotic that is produced by Streptomyces griseus ETH A7796, is an ideal candidate for the synthesis of new antimicrobial drugs. This secondary metabolite is composed of two units of (+)-nonactic acid 49 and two units of (–)- nonactic acid 50. Whereas nonactin does not possess a synthetically useful chemical „handle‟, the nonactic acid subunits do. Through methanolysis of this structure and the separation of the two enantiomers, followed by a series of transformations, easily ii diversifiable scaffolds have been synthesized, which allows for the relatively rapid synthesis of chemically diverse libraries. From a small library of compounds that were synthesized, the compounds, 72 and 71 were found to show promising activities against vancomycin-resistant Enterococcus faecalis (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Compounds 88 and 90 were shown to be the active enantiomers. It was also shown by making the 1,4-substituted triazoles and the 1,5-substituted triazoles 91, 92 that only the 1,4-substituted triazoles gave the aforementioned activities. These results illustrate the vital importance of stereochemistry and regiochemistry. To establish the importance of the nonactic acid moiety itself in the triazoloester compounds, analogues of these compounds were made by replacing the nonactic acid moiety with a cyclohexane moiety, specifically starting with both trans and cis 4-cyclohexanol- carboxylic acid. Neither the cis nor the trans analogues 131, 132, 142, 143, 151, 152, 160, 161 of either of the regioisomers of the compounds made to mimic 72 and 71 gave the activities of their nonactate-containing counterparts. As an alternative to chemical synthesis we investigated biotransformation of nonactic acid analogs by Streptomyces griseus. While we were unable to generate new nonactin analogues we did discover an inhibitor of nonactin biosynthesis 186 and we were able to set limits on precursor directed biosynthesis in S. griseus. iii The Missing Piece In the fire the stone, Turned in the pyre a bone, Seasoned with the spice of ash. In the hearth the cauldron, Melted in the crucible this dust, Out of the brazen kettle, Arose a thing of brain, bone, and flesh. And in the dark stumbled „round, Until the morning light was found, Though by all this amalgam had every part, It fell at the door to dust for lack of a heart. Joshua Bryant Phillips iv Acknowledgements It has been my distinct honor of working with some of the best professionals in the field and I would be truly without merit or consequence if I did not mention nor paid heed to the guidance, knowledge, and humor they have been kind and patient enough to bestow on me. First and foremost I would like to thank Dr. Nigel D. Priestley, my advisor, who has bore the brunt of my daily tribulations in organic chemistry and so eloquently provided much needed insight into its intricacy. I thank you for your generous support during this long and difficult endeavor. The Priestley group, through all its metamorphoses, has been as a charm through my studies, without which none of this would have been possible. I would like to offer my sincere and abiding gratitude to my fellows and friends. James Cox has provided valuable assistance in my research, provided through great labors, methyl (±) nonactate, enantiomerically enriched, enantiomerically pure methyl nonactate, and methyl homononactate, the starting materials in this project, and who taught me a great deal of synthesis. Of Bradley A. Bassette Jr. who is a man of unconquerable vigor and humor and, truly, a man that can be counted upon to come through in a clinch. Brian Kusche has also provided me with a great deal of methyl nonactate and nonactic acid. By imparting his understanding of synthesis and the procedures therein, he has left an indelible mark on my education; for his humor, a smile on face. It would be wantonly neglectful of me not to mention the herculean efforts of the most fair and eminent Ladies, Adrienne E. Smith, Dr. Erin S. Bolstad, and Dr. Brooke Martin who I am grateful to for the testing of these libraries despite their own vast amounts of works before them. It is their unparalleled skill that has v left me envious and pushed me to be ever greater. Rong Jian, a man with a wry and understated humor, who has seen fit to impart to me a wider view of the world. Of P. Whitney Swain III, who has taken pains in helping me with my research, and without who nothing would have been quite the same. And not in the least, Heather Ewing, a great friend, a skilled chemist, and truly a student I have felt proud to have had. I would also like to express my gratitude to my committee members, both past and present who have had great patience with me and have served to push me in the right direction. To Dr.‟s Bruce Bowler, Michelle McGuirl, Holly Thompson, Brooke Martin, Ed Waali, Chris Palmer, and Don Kiely, you have my sincere esteem and thanks for your efforts. And to the faculty, I have appreciated your kindness, your knowledge, and your invaluable wisdom that has led me to where I am today. I would especially like to thank Dr. Earle Adams for his work for the NMR 2D-NOE spectra for the determination of the regiochemistry of the compounds that constitute the triazoloester library. Of course, none of this would have been possible without the love and support of my family through these many years of education. My accomplishments, whatever they may be, either great or small, are also theirs in full measure. For my family, friends, and teachers, thank you for everything. vi TABLE OF CONTENTS LIST OF ABBREVIATIONS………………………………………………………...x LIST OF FIGURES…………………………………………………………………..xi LIST OF SCHEMES………………………………………………………………..xiii LIST OF TABLES…………………………………………………………………..xv 1. INTRODUCTION AND BACKGROUND OF ANTIBIOTICS………………….1 1.1 Origin and history of antibiotics………………………………………………........1 1.1.A Definitions………………………………………………………………………........1 1.1.B Arsenicals and sulfonamides: development of the first synthetic antibiotics…...2 1.1.C Beta-lactam antibiotics……………….……...………………………….…………...5 1.1.D Cephalosporins…………………………………………………………………........8 1.1.E Carbacephems………………………………………………………........................9 1.1.F Carbapenems…………………………………………………………………….….10 1.1.G Monobactams……………………………………………………………………….11 1.1.H Aminoglycosides…………………………………………………………………….11 1.1.I. Macrolides………………………………………………………………………..…12 1.1.J. Ansamycins……………………………………………………………………........16 1.1.K. Tetracyclines……………………………………………………………………...…17 1.1.L. Tigecycline…………………………………………………………………………...19 1.1.M. Glycopeptides…………………………………………………………………….…20 1.1.N. A lipopetide antibiotic, daptomycin…………………………………………….....21 1.1.O. Quinolones and fluoroquinolones……………………………………………….…22 1.1.P. Oxazolidinones……………………………………………………………………...25 1.1.Q. Polypeptide antibiotics…………………………………………………………......26 1.1.R. Chloramphenicol……………………………………………………………………29 1.1.S. Trimethoprim…………………………………………………………………..…...30 1.2 Rise of antibiotic resistant strains…………………………………………..……..30