Chemical Investigation of the Antarctic Marine Invertebrates

282 Pages·2015·6.72 MB·English

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Graduate Theses and Dissertations Graduate School
5-31-2010
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SSyynnooiiccuumm aaddaarreeaannuumm aanndd AArrtteemmiissiinnaa pplluummoossaa
Jaime Heimbegner Noguez
University of South Florida
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Noguez, Jaime Heimbegner, "Chemical Investigation of the Antarctic Marine Invertebrates Synoicum
adareanum and Artemisina plumosa" (2010). Graduate Theses and Dissertations.
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Chemical Investigation of the Antarctic Marine Invertebrates
Synoicum adareanum and Artemisina plumosa

by

Jaime Heimbegner Noguez

A dissertation submitted in partial fulfillment
Of the requirements for the degree of
Doctor of Philosophy
Department of Chemistry
College of Arts and Sciences
University of South Florida

Major Professor: Bill Baker, Ph.D.
Edward Turos, Ph.D.
Roman Manetsch, Ph.D.
Abdul Malik, Ph.D.

Date of Approval:
March 26, 2010

Keywords: organic chemistry, natural products, bioassay, tunicate, sponge

© Copyright 2010, Jaime Heimbegner Noguez
Dedication
This dissertation is dedicated to my husband, Emilio, who stood beside me every
step of the way. His strength and love helped get me through the hard times and made the
good times even more precious. I would also like to dedicate this work to my parents for
helping me to realize my dream and providing me with the means to make it come true.
Without their love, support, and firm belief in the importance of education this work
would not have been possible. And last but certainly not least, I would like to dedicate
this work to my sisters and friends, who always provided a sympathetic ear or much
needed laugh, and helped me to keep things in perspective when life seemed
overwhelming.
Acknowledgments
First and foremost, I must thank my advisor Dr. Bill Baker, for allowing me to be
a part of his incredible research program. He has always inspired me, challenged me, and
perhaps most importantly helped me to realize my potential. Without his support and
guidance this dissertation would hardly be possible. I thank the Florida Center of
Excellence for Biomolecular Identification and Targeted Therapeutics for awarding me
with a Thrust scholarship to help fund some of this research.
I would also like to thank my committee members for their encouragement and
taking the time to help mold me from a young woman with big dreams into a successful
scientist with the tools to achieve them. Thanks to Dr. Dennis Kyle and the members of
his laboratory as well as Leigh West for their assistance with the leishmania and
cytotoxicity assays. I am grateful for your patience and teaching me the molecular
biology techniques pertinent to my research. I owe many thanks to Dr. Xie and the
members of his laboratory at UT Southwestern Medical Center for testing our samples
for v-ATPase activity. And to Dr. Edwin Rivera for his help over the years with the NMR
data acquisition that my research relied heavily on.
And finally, I must thank all of the graduate students, particularly the other
members of the Baker lab, for making my time at the University of South Florida so
enjoyable. Whether it be sharing jokes and funny stories to help the hours pass in the lab
or drinks after a long week of work, you always found a way to remind me of how
fortunate I was to be surrounded by such a great group of people.
Table of Contents
List of Figures iv
List of Tables vi
List of Schemes vii
List of Abbreviations viii
Abstract x
Chapter One. Natural Products as Drug Leads
1.1 Natural Products as Therapeutic Agents 1
1.2 The Impact of Natural Products on the Pharmaceutical Industry 2
1.3 Drugs from the Sea 8
1.4 Cold Water Chemistry 13
1.5 Research Objectives 18

Chapter Two. Chemical Investigation of the Antarctic Tunicate Synoicum adareanum
2.1 Introduction
2.1.1 The Chemistry of Cold Water Tunicates 19
2.1.2 Secondary Metabolites from the Synoicum genus 24
2.2 Chemical Investigation of the Antarctic Tunicate Synoicum adareanum 27
2.2.1 The Palmerolides 28
2.2.2 Ring System “A” Palmerolides 29
i
2.2.2.1 Stereochemical Assignment of Palmerolides D-G 34
2.2.3 Ring System “B” Palmerolides 38
2.2.3.1 Stereochemical Assignment of Palmerolide B and H 41
2.2.4 Ring System “C” Palmerolides 46
2.2.4.1 Stereochemical Assignment of Palmerolides C and K 49
2.3 Structure Activity Relationship Studies of Palmerolide A
2.3.1 Bioactivity of the Palmerolides 52
2.3.2 Structure Activity Relationship Studies of Palmerolide A
via Synthesis 56
2.3.3 Structure Activity Relationship Studies of Palmerolide A
via Derivatization
2.3.3.1 Preparation of Palmerolide A Analogs 58
2.3.3.2 Biological Evaluation of Palmerolide A Analogs 63

Chapter Three. Further Investigation into the Chemical Composition of S.adareanum
3.1 Introduction to Glycosphingolipids 67
3.2 Isolation of Glycosphingolipids from S. adareanum 68
3.3 Structure Elucidation of Glycosphingolipids from S. adareanum 71

Chapter Four. Chemical Investigation of the Antarctic, Orange Encrusting Sponge
Artemisina plumosa
4.1 Introduction to Leishmania 79
4.2 Bioassay-guided fractionation of Artemisina plumosa 82
ii
Chapter Five. Conclusion 88
Chapter Six. Experimental 90
6.1 General Experimental Procedures 90
6.2 Biological Material 91
6.3 Extraction of S.adareanum and Isolation of Secondary Metabolites 91
6.4 Acetylation of Glycosphingolipids from S. adareanum 94
6.5 Preparation of Palmerolide A Analogs 95
6.5.1 Preparation of 107 95
6.5.2 Preparation of 108, 109, 110 96
6.5.3 Preparation of 111 and 112 99
6.7 Cytotoxicity Assay 101
6.8 Leishmania Assay 102
List of References 103
Appendices 118
Appendix A: NMR data tables 119
Appendix B: Selected 1D and 2D NMR data 125
Appendix C: Mass Spectral Data 242
Appendix D: Bioassay Data 254

About the Author End Page
iii
List of Figures
Figure 1. Synoicum adareanum collected at Palmer Station, Antarctica 28
Figure 2. Comparison of palmerolide D and palmerolide A 13C NMR
chemical shifts 31
Figure 3. Comparison of palmerolide E and palmerolide A 13C NMR
chemical shifts 32
Figure 4. Comparison of palmerolide F and palmerolide A 13C NMR
chemical shifts 33
Figure 5. Comparison of palmerolide G and palmerolide A 13C NMR
chemical shifts 33
Figure 6. Mosher’s depiction of the MTPA plane of an MTPA ester 34
Figure 7. Palmerolide F (R) –MTPA diester in d -DMSO 35
6
Figure 8. Palmerolide F (S) –MTPA diester in d -DMSO 36
6
Figure 9. Comparison of palmerolide B and palmerolide A 13C NMR
chemical shifts 40
Figure 10. Comparison of palmerolide B and palmerolide H 13C NMR
chemical shifts 40
Figure 11. Comparison of palmerolide H and palmerolide D 13C NMR
chemical shifts 40
Figure 12. Newman projection of palmerolide B C-7/C-8 stereocenters 44
iv
Figure 13. Comparison of palmerolide C and palmerolide A 13C NMR
chemical shifts 47
Figure 14. Comparison of palmerolide Cand palmerolide K 13C NMR
chemical shifts 48
Figure 15. Comparison of palmerolide K and palmerolide E 13C NMR
chemical shifts 48
Figure 16. Newman projection of palmerolide C C-8/C-9
and C-9/C-10 stereocenters 50
Figure 17. 1H NMR spectrum of palmerolide A hydrogenation product 58
Figure 18. 1H NMR spectrum of palmerolide A C-7 p-bromobenzoate 59
Figure 19. 1H NMR spectrum of palmerolide A C-10 p-bromobenzoate 60
Figure 20. 1H NMR spectrum of palmerolide A C-7/C-10 p-bromobenzoates 60
Figure 21. 1H NMR spectrum of palmerolide A C-11 alcohol 62
Figure 22. 1H NMR spectrum of palmerolide A C-3 alcohol 62
Figure 23. Basic structural units of glycosphingolipids 67
Figure 24. 1H NMR spectrum of glycosphingolipid 113a in d -DMSO 71
6
Figure 25. Comparison of β-galactopyranoside and β-glucopyranoside 74
Figure 26. The most characteristic fragment ions in the APCI-MS data of 113a 74
Figure 27. 1H NMR spectrum of glycosphingolipd 114a-b in d -DMSO 77
6
Figure 28. 1H NMR spectrum of steroid series 1 in CDCl 83
3
Figure 29. 1H NMR spectrum of steroid series 2 in CDCl 83
3
Figure 30. 1H NMR spectrum of steroid series 3 in CDCl 84
3
Figure 31. Steroid nuclei and side chains found in Artemisina plumosa 86
v
List of Tables
Table 1. Stereochemical analysis (Δδ) of palmerolides A-G using
Mosher’s method 36
Table 2. 3J (Hz) analysis of key palmerolide stereocenters in
H,H
palmerolides A-G 38
Table 3. 3J (Hz) analysis of key palmerolide stereocenters in
H,H
palmerolides A, B, H 41
Table 4. 3J and 2,3J (Hz) values for anti and gauche orientations
H,H C,H
in acyclic systems 42
Table 5. 3J and 2,3J (Hz) values for palmerolides B and H 43
H,H C,H
Table 6. Stereochemical analysis (Δδ) of palmerolide B using Mosher’s method 45
Table 7. 3J (Hz) analysis of key palmerolde stereocenters in
H,H
palmerolides A and C 48
Table 8. 3J and 2,3J (Hz) values for palmerolide C 49
H,H C,H
Table 9. Stereochemical analysis (Δδ) of palmerolide C using Mosher’s method 50
Table 10. 3J (Hz) analysis of key palmerolde stereocenters in
H,H
palmerolides C and K 50
Table 11. Bioactivity data for the palmerolides 52
Table 12. Bioactivity data for palmerolide A analogs 61
Table 13. Calculated coupling constants of sugar protons 71
vi