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VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY UNIVERSITY OF SCIENCE NGUYEN THI HOAI THU STUDY ON CHEMICAL CONSTITUENTS AND BIOACTIVITIES OF SONNERATIA ALBA AND SONNERATIA OVATA (SONNERATIACEAE) GROWING IN CAN GIO MANGROVE FOREST – HO CHI MINH CITY DOCTORAL THESIS IN CHEMISTRY Ho Chi Minh City, 2015 VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY UNIVERSITY OF SCIENCE NGUYEN THI HOAI THU STUDY ON CHEMICAL CONSTITUENTS AND BIOACTIVITIES OF SONNERATIA ALBA AND SONNERATIA OVATA (SONNERATIACEAE) GROWING IN CAN GIO MANGROVE FOREST – HO CHI MINH CITY Speciality: Code: Organic chemistry 62 44 27 01 Examination board: Assoc Prof Dr Tran Hung (1st Reviewer) Assoc Prof Dr Tran Cong Luan Assoc Prof Dr Pham Dinh Hung Assoc Prof Dr Phan Minh Giang Dr Tran Thi Phuong Thao (2nd Reviewer) (3rd Reviewer) (1st Independent Reviewer) (2nd Independent Reviewer) SUPERVISORS: PROF NGUYEN KIM PHI PHUNG PROF POUL ERIK HANSEN Ho Chi Minh City, 2015 ORIGINALITY STATEMENT The work presented in this thesis was completed in the period of September 2010 to September 2014 under the co-supervision of Professor Nguyen Kim Phi Phung, University of Science, Vietnam National University, Ho Chi Minh City, and Professor Poul Erik Hansen, Roskilde University, Denmark In compliance with the university regulations, I declare that: Except where due acknowledgement has been made, the work is that of the author alone The work has not been submitted previously, in whole or in part, to qualify for any other academic award The content of the thesis is the result of work which has been carried out since the official commencement date of the approved PhD study program Ethic procedures and guidelines have been followed Ho Chi Minh City, June 2015 PhD Candidate NGUYEN THI HOAI THU i ACKNOWLEDGEMENTS First and foremost, I offer my sincerest gratitude to my supervisor Prof Nguyen Kim Phi Phung, who has been supporting me throughout the course of my research with her patience, kindness, invaluable advice, guidance, encouragement and comments I would also like to greatly acknowledge Prof Poul Erik Hansen, my Co-supervisor, for his kind scientific guidance, support, and suggestions to my study In addition, I am indebted to Dr Vo Van Chi and the deceased Pharmacist Phan Duc Binh, who provided me with the scientific name of the four species in the Sonneratia and Avicennia genera I am thankful to Dr Le Duc Tuan, from the Management Board for HCMC Environmental Protection Forests, for his help, kindness and advice during my plant sample collection I would like to acknowledge the encouragement and insightful comments from the rest of the Examination Board Special thanks go to the Foreign Language Center of the University of Science for their editing of the English version of my work I would like to acknowledge the Department of Science and Technology – Ho Chi Minh City for supporting me Additionally, I would like to thank all my friends at the Department of Organic Chemistry Laboratory, University of Science, for providing me with their constant encouragement Finally, an honorable mention goes to my family and friends, without whose understanding and support this thesis would not have been completed successfully ii TABLE OF CONTENTS i ACKNOWLEDGEMENTS TABLE OF CONTENTS iii LIST OF ABBREVIATIONS vi viii LIST OF TABLES LIST OF FIGURES AND SCHEMES ix INTRODUCTION Chapter LITERATURE REVIEW 1.1 Sonneratia genus – Botanical description 1.1.1 Sonneratia alba J E Smith 1.1.2 Sonneratia ovata Backer 1.2 Chemical studies of some species of Sonneratia genus 1.2.1 Sonneratia alba J E Smith 1.2.2 Sonneratia ovata Backer 1.2.3 Sonneratia caseolaris L Engl 1.2.4 Sonneratia apetala Buch Ham 1.2.5 Sonneratia hainanensis W.C.Ko, E.Y Chen & W.Y Chen 1.2.6 Sonneratia paracaseolaris W.C.Ko, E.Y Chen & W.Y Chen 1.3 Pharmacological studies of some species of Sonneratia genus 1.3.1 Sonneratia alba J E Smith 1.3.2 Sonneratia ovata Backer 1.3.3 Sonneratia caseolaris L Engl 11 Chapter EXPERIMENTAL 2.1 General experimental procedures 11 2.2 Plant material 12 2.3 Extraction and isolation 13 2.4 Theoretical calculations 16 2.5 Acid hydrolysis of 94 and 98 17 2.6 Biological assays 17 Chapter RESULTS AND DISCUSSION 3.1 Chemical structure elucidation 24 24 3.1.1 Chemical structure of steroids (Group A) iii 24 3.1.1.1 Structure elucidation of 3.1.1.2 Structure elucidation of 3.1.1.3 Structure elucidation of 3.1.2 Chemical structure of triterpenoids (Group B) 24 25 27 28 3.1.2.1 Structure elucidation of 20 3.1.2.2 Structure elucidation of 21 3.1.2.3 Structure elucidation of 55 3.1.2.4 Structure elucidation of 25 3.1.2.5 Structure elucidation of 12 3.1.2.6 Structure elucidation of 14 3.1.2.7 Structure elucidation of 56 3.1.2.8 Structure elucidation of 57 3.1.3 Chemical structure of flavonoids (Group C) 28 29 30 32 34 35 37 38 38 3.1.3.1 Structure elucidation of 40 3.1.3.2 Structure elucidation of 41 3.1.3.3 Structure elucidation of 58 3.1.3.4 Structure elucidation of 59 3.1.3.5 Structure elucidation of 60 3.1.3.6 Structure elucidation of 61 3.1.3.7 Structure elucidation of 62 3.1.3.8 Structure elucidation of 63 3.1.4 Chemical structure of lignans (Group D) 38 40 42 43 44 46 47 48 49 3.1.4.1 Structure elucidation of 64 3.1.4.2 Structure elucidation of 65 3.1.4.3 Structure elucidation of 66 3.1.4.4 Structure elucidation of 67 3.1.4.5 Structure elucidation of 68 3.1.4.6 Structure elucidation of 69 3.1.4.7 Structure elucidation of 70 3.1.4.8 Structure elucidation of 71 3.1.4.9 Structure elucidation of 72 3.1.4.10 Structure elucidation of 73 3.1.5 Chemical structure of megastigmanes (Group E) 49 52 53 55 57 58 59 61 63 64 65 3.1.5.1 Structure elucidation of 74a and 74b 3.1.5.2 Structure elucidation of 75 3.1.5.3 Structure elucidation of 76 3.1.5.4 Structure elucidation of 77 3.1.5.5 Structure elucidation of 78 iv 65 67 70 71 73 3.1.5.6 Structure elucidation of 79 3.1.5.7 Structure elucidation of 80 3.1.5.8 Structure elucidation of 81 3.1.5.9 Structure elucidation of 82 3.1.5.10 Structure elucidation of 83 3.1.5.11 Structure elucidation of 84 3.1.5.12 Structure elucidation of 85 3.1.6 Chemical structure of phenolics (Group F) 75 79 80 82 83 85 86 87 3.1.6.1 Structure elucidation of 86 3.1.6.2 Structure elucidation of 26 3.1.6.3 Structure elucidation of 87 3.1.6.4 Structure elucidation of 88 3.1.6.5 Structure elucidation of 89 3.1.6.6 Structure elucidation of 30 3.1.6.7 Structure elucidation of 33 3.1.6.8 Structure elucidation of 90 3.1.6.9 Structure elucidation of 91 3.1.6.10 Structure elucidation of 92 3.1.6.11 Structure elucidation of 93 3.1.6.12 Structure elucidation of 94 3.1.6.13 Structure elucidation of 95 3.1.7 Chemical structure of other compounds (Group G) 87 91 92 94 96 98 98 99 100 101 102 104 106 107 3.1.7.1 Structure elucidation of 46 3.1.7.2 Structure elucidation of 96 3.1.7.3 Structure elucidation of 97 3.1.7.4 Structure elucidation of 98 3.1.8 Discussion on the phytochemistry of Sonneratia species 107 107 108 110 113 3.2 Biological activities of extracts and isolated compounds 120 3.2.1 Cytotoxic activity against three cancer cell lines 120 3.2.2 Inhibitory effect on acetylcholinesterase activity 123 Chapter CONCLUSION 126 LIST OF PUBLICATIONS 128 REFERENCES 129 APPENDICES v LIST OF ABBREVIATIONS 1D/2D–NMR : One/Two–Dimensional–Nuclear Magnetic Resonance AChE : Acetylcholinesterase BChE : Butyrylcholinesterase brd : Broad doublet brs : Broad singlet calcd : calculated CC : Column Chromatography COSY : Correlation Spectroscopy d : Doublet dd : Doublet of doublets ddd : Doublet of doublet of doublets DMSO : Dimethyl sulfoxide DEPT : Distortionless Enhancement by Polarization Transfer DPPH : 1,1–Diphenyl–2–picrylhydrazyl GIAO : Gauge Including Atomic Orbital Glc : Glucose h : hour HMBC : Heteronuclear Multiple Bond Correlation HSQC : Heteronuclear Single Quantum Correlation HPLC : High Performance Liquid Chromatography HR–ESI–MS : High Resolution–Electrospray Ionization–Mass Spectrometry J : Coupling constant GC–MS : Gas Chromatography–Mass Spectrometry LC : Liquid Chromatography m : Multiplet mp : melting point vi m/z : Mass to charge ratio NMR : Nuclear Magnetic Resonance NOESY : Nuclear Overhauser Effect Spectroscopy ppm : Part per million RP–C18 : Reversed Phase silica gel C18 s : Singlet S : Sonneratia TLC : Thin–Layer Chromatography t : Triplet UV–VIS : Ultraviolet Visible [α]D : Specific rotation o : Degree Celcius C vii LIST OF TABLES Page Table 3.1 NMR spectroscopic data of compounds 2, and 26 Table 3.2 13 31 Table 3.3 H–NMR data of compounds 20, 21, 55 and 25 33 Table 3.4 H–NMR data of compounds 12, 14, 56 and 57 36 Table 3.5 13 Table 3.6 H–NMR data of compounds 40, 41, 58 and 59 41 Table 3.7 H–NMR data of compounds 60–63 46 Table 3.8 13 Table 3.9 C–NMR data of compounds 20, 21, 55, 25, 12, 14, 56 and 57 C–NMR data of compounds 40, 41, 58–63 41 C–NMR data of compounds 64–73 51 H–NMR data of compounds 64–68 52 Table 3.10 H–NMR data of compounds 69–73 59 Table 3.11 13 Table 3.12 C–NMR data of compounds 74–85 68 H–NMR data of compounds 74–77 69 Table 3.13 H–NMR data of compounds 78–80 75 Table 3.14 H–NMR data of compounds 81–85 83 Table 3.15 13 Table 3.16 Table 3.17 13 Table 3.18 H–NMR data of compounds 89, 30, 33, 81–92 Table 3.19 H–NMR data of compounds 93–95 and 46 C–NMR data of compound 26 and the new ones 86–88 90 H–NMR data of compound 26 and the new ones 86–88 90 C–NMR data of 89, 30, 33, 90–95 97 97 103 Table 3.20 NMR data of compounds 46, 96–98 109 Table 3.21 Cytotoxic activities against three cancer cell lines of isolated 121 compounds Table 3.22 The IC50 values of cytotoxic activities against three cancer cell 122 lines of some isolated compounds Table 3.23 Acetylcholinesterase inhibition acitivities of some extracts and isolated compounds viii 124 App 98 Appendix 53.4 13C-NMR (125 MHz) spectrum of 94 in deuterium oxide 20.47 29.87 37.50 60.67 76.67 75.85 75.75 73.29 69.63 101.48 120.59 116.23 116.21 143.84 141.75 135.35 Appendix 53.3 1H-NMR (500 MHz) spectrum of 94 in deuterium oxide 3.01 2.15 2.04 2.09 1.16 1.06 2.14 1.05 1.14 1.04 1.00 1.00 3.543 3.525 3.507 3.771 3.761 3.747 3.736 3.945 3.933 3.909 6.791 6.787 6.775 6.771 6.923 6.907 6.880 6.877 1.330 1.317 1.908 1.806 2.664 2.648 2.633 3.316 3.300 3.298 3.282 4.510 4.494 f1 (ppm) Appendix 53.5 COSY-NMR spectrum of 94 in deuterium oxide Appendix 53.6 HSQC-NMR spectrum of 94 in deuterium oxide App 99 2.557 2.531 1.646 1.629 1.149 1.133 1.25 1.09 1.08 2.17 3.23 6.530 6.525 6.510 6.505 6.716 6.696 6.689 7.737 3.747 3.732 3.716 3.701 1.93 1.00 1.19 Appendix 53.7 HMBC-NMR spectrum of 94 in deuterium oxide Appendix 54.1 1H-NMR (400 MHz) spectrum of 95 in acetone-d6 App 100 f1 (ppm) 42.28 32.18 23.94 67.09 120.32 116.27 115.92 145.72 143.75 135.15 6' 2' 5' 4' 3' 210 200 190 180 170 160 150 140 1' 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 13 f1 (ppm) Appendix 54.2 C-NMR (100 MHz) spectrum of 95 in acetone-d6 Appendix 54.3 HSQC-NMR spectrum of 95 in acetone-d6 App 101 1.94 1.00 0.99 1.00 3.882 3.876 3.700 3.277 3.220 4.954 4.915 4.686 4.647 4.367 4.342 1.83 2.67 1.02 1.08 7.410 7.408 7.405 7.331 7.328 Appendix 54.4 HMBC-NMR spectrum of 95 in acetone-d6 Appendix 55.1 1H-NMR (300 MHz) spectrum of 46 in methanol-d4 App 102 1' 4' 3' 5' 6' 2' 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 13 1.628 1.602 1.483 1.232 1.211 0.965 0.940 0.915 Appendix 56.1 1H-NMR (300 MHz) spectrum of 96 in methanol-d4 App 103 2.90 3.689 3.671 3.649 3.631 1.09 1.02 2.57 1.95 1.10 1.15 1.04 1.25 1.00 3.877 3.870 3.837 3.830 3.798 3.778 3.757 3.737 3.254 3.178 3.152 3.148 3.122 4.343 4.317 Appendix 55.2 C-NMR (75 MHz) spectrum of 46 in methanol-d4 10 5' 1' 105 3' 100 95 90 85 80 2' 4' 75 6' 70 65 60 55 50 45 40 35 30 25 13 Appendix 56.2 C-NMR (75 MHz) spectrum of 96 in methanol-d4 m/z = 353.2689 Calcd for C19H38O4Na, 353.2662 Appendix 57.1 HR-ESI-MS spectrum of 97 App 104 20 15 10 1.616 1.282 1.247 0.884 0.871 0.857 2.353 2.338 2.323 1b 3.701 3.694 3.678 3.671 3.604 3.592 3.581 3.569 3.928 3.919 3.910 4.199 4.190 4.176 4.166 4.155 4.143 4.132 4.119 7.260 1a 3a 3b 16' 4.20 4.10 4.00 3.90 3.80 3.70 3.60 2' 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 3.28 26.58 2.43 2.35 2.07 1.02 1.00 1.01 3' 1.0 0.5 Appendix 57.2 H-NMR (500 MHz) spectrum of 97 in chloroform-d 3' 2' 14' 15' 16' 1' 180 170 160 150 140 13 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 Appendix 57.3 C-NMR (125 MHz) spectrum of 97 in chloroform-d App 105 30 20 10 Appendix 57.4 HSQC-NMR spectrum of 97 in chloroform-d 2' 1a 1b 16' 3' 3a 3b 10 16' 15' 3' 20 30 2' 40 50 60 70 80 90 100 110 120 130 140 150 160 170 1' 180 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 f2 (ppm) 2.2 2.0 1.8 1.6 Appendix 57.5 HMBC-NMR spectrum of 97 in chloroform-d App 106 1.4 1.2 1.0 0.8 0.6 m/z 736.5346 Calcd for C40H75O9N + Na, 736.5340 Appendix 58.1 HR-ESI-MS spectrum of 98 Appendix 58.2 ESI-MS/MS spectrum of 98 App 107 Appendix 58.3 GC-MS chromatogram of 98A App 108 m/z 298.2744 Calcd for C18H35O2N + H, 298.2746 Appendix 58.4 HR-ESI-MS spectrum of 98B Appendix 58.5 IR spectrum of 98 App 109 190 180 OH HO HO 170 O 6'' 2'' 160 O HN OH 1'' O 150 140 1' 14 130 120 110 100 f1 (ppm) 2' 13 1'' 90 App 110 14 3'' 5'' 13 2'' 4'' 1' 80 70 6'' 60 50 33.64 33.31 33.05 30.81 30.76 30.45 23.71 14.44 77.96 77.93 74.99 73.13 72.89 71.60 69.75 62.70 54.71 104.70 134.38 131.98 131.18 130.65 177.24 Appendix 58.6 1H-NMR (500 MHz) spectrum of 98 in chloroform-d:methanol-d4 OH 18 16' OH Sonnercerebroside (98) New compound 16 14' 40 17 15' 30 20 18 16' 15 3' 4' 10 Appendix 58.7 13C-NMR (125MHz) spectrum of 98 in chloroform-d:methanol-d4 6.48 1.05 1.14 2.24 39.77 0.50 3.15 0.72 1.40 1.03 1.89 1.05 1.00 1.97 1.96 1.07 2.08 0.96 0.95 1.31 0.43 0.917 0.903 0.889 1.705 1.549 1.417 1.293 4.282 4.266 4.137 4.116 4.105 4.003 3.996 3.988 3.980 3.883 3.880 3.859 3.727 3.720 3.706 3.362 3.344 3.289 3.215 3.199 3.196 2.075 3.181 1.989 5.503 5.488 5.472 5.458 5.431 5.754 5.752 5.723 5.721 f1 (ppm) f1 (ppm) Appendix 58.8 COSY-NMR spectrum of 98 in chloroform-d:methanol-d4 Appendix 58.9 HSQC-NMR spectrum of 98 in chloroform-d:methanol-d4 App 111 Appendix 58.10 HMBC-NMR spectrum of 98 in chloroform-d:methanol-d4 App 112 ... SONNERATIA ALBA J.E SMITH Vietnamese name: Bần trắng (Figure 2.1) The leaves of Sonneratia abla were collected in Can Gio mangrove forest in Ho Chi Minh city, Vietnam in December 2009 The scientific... National University–Ho Chi Minh City Figure 2.1 Sonneratia alba J.E Smith Figure 2.2 Sonneratia ovata Backer 2.2.2 PLANT MATERIAL FROM SONNERATIA OVATA BACKER Vietnamese name: Bần ổi (Figure 2.2) 12... constituents and bioactivities of Sonneratia alba and Sonneratia ovata (Sonneratiaceae) growing in Can Gio mangrove forest – Ho Chi Minh City” aimed to achieve the following objectives Objectives
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