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Synthesis of Peptides with Hydroxamic Acid Side Chain Appendages University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 12-2003 Synthesis of peptides with hydroxamic acid side chain appendages. Yingchuan Susan Sun 1975- University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Recommended Citation Sun, Yingchuan Susan 1975-, "Synthesis of peptides with hydroxamic acid side chain appendages." (2003). Electronic Theses and Dissertations. Paper 1407. https://doi.org/10.18297/etd/1407 This Master's Thesis is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. SYNTHESIS OF PEPTIDES WITH HYDROXAMIC ACID SIDE CHAIN APPENDAGES By Yingchuan Susan Sun B.S., China Pharmaceutical University, 1997 A Thesis Submitted to the Faculty of the Graduate School of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Master of Science Department of Chemistry University of Louisville Louiville, Kentucky December, 2003 SYNTHESIS OF PEPTIDES WITH HYDROXAMIC ACID SIDE CHAIN APPENDAGES By Yingchuan Susan Sun A Thesis Approved on April 14, 2003 By the Following Thesis Committee: Arno F. Spatola (deceased) Thesis Director Chairman ii Copyright 2003 by Yingchuan Susan Sun All rights reserved DEDICATION This thesis is dedicated to my graduate advisor Dr. Arno Spatola who spent his whole life in teaching me and other students principles of chemical science III ACKNOWLEDGEMENTS The author would like to express her gratitude and appreciation to her mentor, Dr. Arno F. Spatola, for his guidance, advice, encouragement, and inspiration throughout her entire graduate student program. His life-long dedication to career and obligation to students and family is greatly acknowledged and appreciated. The author is also grateful to other members of her master of science committee, Dr. Robert Buchanan, Dr. William Pierce and Dr. K. Grant Taylor for their time and effort in evaluation of this thesis. The effort of our collaborators, Ned Smith, lab manager and Dr. William Pierce, director of the mass spectrometry core laboratory at the University of Louisville, is gratefully acknowledged. It was through their work that the electrospray ionization-mass spectrometry data was obtained. The author also gives thanks to Dr. Hynda Kleinman, Chief, Cell Biology Section, National Institute of Dental and Craniofacial Research, NIH, who provided biological data for this project. She would also like to thank the Graduate School for financial support through the course of these studies. Many laboratory colleagues are acknowledged here for their advice, encouragement and friendships, and they are Dr. Peter Romanovskis, Dr. David Vogel, Dr. Florence BruneI, Ms. Anne-Marie Leudc, Mr. Amit Galande, Ms. Natali Richter, Ms. Elizabeth Romaine-Schmidt and Ms. Melody Grapperhaus who helped the author in preparing a poster and slides. At last the author would like to show her profound gratitude to her parents for their love, support and encouragement. IV ABSTRACT SYNTHESIS OF PEPTIDES WITH HYDROXAMIC ACID SIDE CHAIN APPENDAGES Yingchuan Susan Sun April 14, 2003 Chapter 1 detailed the synthesis method of hydroxamate peptides derivatives of pentapeptide Ac-PHSXX'-N-NH2 by solid phase hydroxamate peptide synthesis method. The glutamic acid / aspartic acid side chain was modified to hydroxamic acid by on resin N-C coupling. The hydroxamate benzyl protecting group was removed during HF cleavage. In Chapter 2 a novel multiple hydroxamic acid peptide siderophore was prepared and the metal binding activity of these peptides was studied by ESI-MS and MS/MS. Siderophore peptide Ac-GlYI-Glu2(NHOH)-D-Pro3-GlY4-Glus(NHOH)-D-Pr06-NH2 was found to have significant preference to Fe(IH) over Zn(H) and Ni(II), while the natural peptide analogue Ac-GlYI-Glu2-D-Pro3-GlY4-Glus-D-Pro6-NH2 did not show any obvious preference in these metal ions. The study of these multi hydroxamate ligands metal coordination revealed that the C-terminal binding site (Glus(NHOH)) has the stronger chelation capability than the N terminal (Glu2(NHOH)) metal binding site and the amide bonds between glutamic acid and proline were identified as the most fragile bonds by MS/MS study. v TABLE OF CONTENTS PAGE ACKNOWLEDGMENTS......... .................. ............... .............. ...... .... IV ABSTRACT................................................................................. V LIST OF TABLES.............................................................................. Xl LIS1' OF FIGURES............................................................ ...... ... .... XlI Chapter 1: Design an Synthesis of the Hydroxamic Acid Variants of Anti- tumorigenic and Antimetastatic Hydroxamate Based Ac-PHSXX'- NH2 Sequences ............................................................... A. Introduction .................................................................... 1. Biological Importance of Peptide PHSRN... ...... ...... ............... 1 2. Preparation of HydroxamicAcid.......................................... 7 B. Research Objectives... ... .................................................. .... 12 c. Results and Discussion..................................................... ... 13 1. Synthesis of Amino Hydroxamate Building Blocks............ ..... ... 13 2. Attempted Synthesis of Pep tides Using a Protected Hydroxamic Acid- Containing Amino Acid as a Preformed Building Block. ..... 16 3. Solid Phase Synthesis of Side Chain Hydroxamic Acid Peptides.... 17 4. Aspartimide Inhibition Study of Ac-PHSD(NHOH)N-NH2 ......... 21 VI 5. Parallel Synthesis of Ac-PHSXX' -NH2 Peptides....................... 30 6. Biological activity tests of peptide analogues Ac-PHSXX'N-NH2... 31 D. Conclusion..................................................................... 34 E. Experimental Section.......................................................... 35 1. Preparation of Boc-Asp(NHOBn)-OFm and Boc-Glu(NHOBn)- OFm........................................................................... 35 (1). Preparation ofBoc-Asp-OH... ......... ....................... ..... 35 (2). Preparation of Boc-Aspartic Acid Anhydride.................... 36 (3). Preparation ofBoc-Asp-OFm...................................... 37 (4). Preparation ofBoc-Glu(OBn)-OFm......... ...................... 37 (5). Preparation ofBoc-Glu-OFm........................... ........... 38 (6). Preparation of Boc-Asp(NHOBn)-OFm.. .................... ..... 39 (7). Preparation of Boc-Glu(NHOBn)-OFm........................... 39 2. Preparation of Boc-Asp(NHOBn)-OH and Boc-Glu(NHOBn)-OH.. 40 (1). Preparation of Boc-Asp(NHOBn)-OH. ........................... 40 (2). Preparation of Boc-Glu(NHOBn)-OH. ........................ .... 41 3. Preparation of Ac-PHSXX'-NH2 sequences........................ ..... 43 (1). Preparation of Ac-Pro-His-Ser-Arg-Asn-NH2.................... 43 (2). Preparation of Ac-Pro-His-Ser-Cys-Asn-NH2.................... 44 (3). Preparation of Ac-Pro-His-Ser-Ser-Asn-NH2..................... 45 (4). Parallel Synthesis of Ac-Pro-His-Ser-Asp-Asn-NH2, Ac-Pro-His-Ser-Asp- Phe-NH2, Ac-Pro-His-Ser-Arg-Phe­ NH2, Ac-Pro-His-Ser-Arg-Try-NH2, Ac-Pro-His-Ser-Cys- Vll Phe-NH2 and Ac-Pro-His-Ser-Cys-Tyr-NH2..................... 46 (5). Preparation of Ac-Pro-His-Ser-Glu(NHOH)-Leu-NH2 ......... 49 (6). Preparation of Ac-Pro-His-Ser-Glu(NHOH)-Asn-NH2......... 50 (7). Preparation of Ac-Pro-His-Ser-Asp(NHOH)-Asn-NH2......... 51 Chapter II: Synthesis and Metal Binding Studies of Peptides Siderophore Analogues............................................. ......................... 52 A. Introduction... ............................................. ..................... 52 1. General Introduction to Siderophores.................................... 52 2. Molecular Diversity of Siderophores..................................... 54 (1). Hydroxamate Siderophores.......................................... 54 (2). Phenolate Siderophores.................................... .......... 55 (3). Mixed Metal Binding Sites Siderophores......................... 56 (4). Carboxylate Siderophores........................................... 58 (5). Peptide Siderophores................................................ 59 3. Siderophore Detection................................................ ...... 61 4. Methods for Metal Binding Assay............ ........................... 61 (1). Electron Spray Ionization- Mass Spectrometry (ESI-MS)...... 62 (2). Tandem Mass Spectrometry (MS/MS)........................... 63 (3). Matrix Assisted Laser Desorption Ionization - Time of Flight Mass Spectrometry (MALDI-TOF MS)......................... 64 B. Research Objectives.......................................... ............ ..... 66 C. Results and Discussion. .. .. 66 1. Peptide Synthesis........................................................ ... 66 Vlll 2. Metal Binding Study with Peptide E (Ac-GlYI-Glu2-D-Pro3-GlY4- Glu5-D-Pro6-NH2) Using MALDI-TOF MS......... ............... 69 3. Metal Binding Study of Peptide E (Ac-GlYI-Glu2-D-Pro3-G1Y4- 72 Glu5-D-Pro6-NH2) with ESI-MS ................................... .. (I).Peptide E Binding with Single Metal Studies........ ............
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